同: (遺伝子)p53 gene p53遺伝子; (蛋白質)p53 protein p53蛋白質

p53遺伝子

癌抑制遺伝子

MDM2はp53と結合して安定化し、ユビキチン化を介してP53の分解に導く
活性化ATM(DNA損傷などが引き金となる)はp53をリン酸化する
リン酸化されたp53は次の経路を活性化する

→Bax→アポトーシス

→p21^WAP1/CII1→細胞周期停止

→GADD45

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p53(蛋白質)=

Tumor protein p53
	; PDB rendering based on 1TUP: P53 complexed with DNA
Available structures
PDB	Ortholog search: PDBe, RCSB
List of PDB id codes
	1A1U, 1AIE, 1C26, 1DT7, 1GZH, 1H26, 1HS5, 1JSP, 1KZY, 1MA3, 1OLG, 1OLH, 1PES, 1PET, 1SAE, 1SAF, 1SAK, 1SAL, 1TSR, 1TUP, 1UOL, 1XQH, 1YC5, 1YCQ, 1YCR, 1YCS, 2AC0, 2ADY, 2AHI, 2ATA, 2B3G, 2BIM, 2BIN, 2BIO, 2BIP, 2BIQ, 2FEJ, 2FOO, 2GS0, 2H1L, 2H2D, 2H2F, 2H4F, 2H4H, 2H4J, 2H59, 2J0Z, 2J10, 2J11, 2J1W, 2J1X, 2J1Y, 2J1Z, 2J20, 2J21, 2K8F, 2L14, 2LY4, 2OCJ, 2PCX, 2VUK, 2WGX, 2X0U, 2X0V, 2X0W, 2XWR, 2YBG, 2YDR, 2Z5S, 2Z5T, 3D05, 3D06, 3D07, 3D08, 3D09, 3D0A, 3DAB, 3DAC, 3IGK, 3IGL, 3KMD, 3KZ8, 3LW1, 3OQ5, 3PDH, 3Q01, 3Q05, 3Q06, 3SAK, 3TG5, 3TS8, 3ZME, 4AGL, 4AGM, 4AGN, 4AGO, 4AGP, 4AGQ, 4BUZ, 4BV2, 4FZ3, 4HFZ, 4HJE, 4IBQ, 4IBS, 4IBT, 4IBU, 4IBV, 4IBW, 4IBY, 4IBZ, 4IJT, 4KVP, 4LO9, 4LOE, 4LOF
Identifiers
Symbols	TP53; BCC7; LFS1; P53; TRP53
External IDs	OMIM: 191170 MGI: 98834 HomoloGene: 460 ChEMBL: 4096 GeneCards: TP53 Gene
Gene Ontology
Molecular function	• RNA polymerase II core promoter proximal region sequence-specific DNA binding transcription factor activity involved in positive regulation of transcription; • RNA polymerase II transcription factor binding; • RNA polymerase II transcription regulatory region sequence-specific DNA binding transcription factor activity involved in positive regulation of transcription; • protease binding; • p53 binding; • DNA binding; • chromatin binding; • damaged DNA binding; • sequence-specific DNA binding transcription factor activity; • copper ion binding; • protein binding; • ATP binding; • transcription factor binding; • zinc ion binding; • enzyme binding; • protein kinase binding; • receptor tyrosine kinase binding; • ubiquitin protein ligase binding; • histone deacetylase regulator activity; • histone acetyltransferase binding; • identical protein binding; • transcription regulatory region DNA binding; • protein heterodimerization activity; • protein N-terminus binding; • chaperone binding; • protein phosphatase 2A binding; • MDM2/MDM4 family protein binding;
Cellular component	• chromatin; • nuclear chromatin; • nucleus; • nucleoplasm; • replication fork; • transcription factor TFIID complex; • nucleolus; • cytoplasm; • mitochondrion; • mitochondrial matrix; • endoplasmic reticulum; • cytosol; • nuclear matrix; • nuclear body; • PML body; • protein complex;
Biological process	• protein import into nucleus, translocation; • cell cycle checkpoint; • negative regulation of transcription from RNA polymerase II promoter; • DNA strand renaturation; • in utero embryonic development; • somitogenesis; • release of cytochrome c from mitochondria; • T cell proliferation involved in immune response; • B cell lineage commitment; • T cell lineage commitment; • base-excision repair; • nucleotide-excision repair; • double-strand break repair; • regulation of transcription, DNA-dependent; • protein complex assembly; • apoptotic process; • induction of apoptosis; • response to DNA damage stimulus; • DNA damage response, signal transduction by p53 class mediator resulting in cell cycle arrest; • DNA damage response, signal transduction by p53 class mediator resulting in transcription of p21 class mediator; • ER overload response; • cell cycle arrest; • transforming growth factor beta receptor signaling pathway; • Ras protein signal transduction; • multicellular organismal development; • gastrulation; • negative regulation of neuroblast proliferation; • central nervous system development; • cell aging; • blood coagulation; • protein localization; • negative regulation of DNA replication; • cell proliferation; • negative regulation of cell proliferation; • determination of adult lifespan; • rRNA transcription; • response to salt stress; • response to X-ray; • response to gamma radiation; • virus-host interaction; • cell differentiation; • negative regulation of cell growth; • DNA damage response, signal transduction by p53 class mediator; • negative regulation of transforming growth factor beta receptor signaling pathway; • positive regulation of histone deacetylation; • mitotic G1 DNA damage checkpoint; • positive regulation of protein oligomerization; • T cell differentiation in thymus; • cellular protein localization; • cellular response to UV; • multicellular organism growth; • cellular response to drug; • cellular response to glucose starvation; • intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator; • regulation of apoptotic process; • positive regulation of apoptotic process; • negative regulation of apoptotic process; • positive regulation of neuron apoptotic process; • negative regulation of transcription, DNA-dependent; • positive regulation of transcription, DNA-dependent; • positive regulation of transcription from RNA polymerase II promoter; • response to antibiotic; • regulation of mitochondrial membrane permeability; • negative regulation of fibroblast proliferation; • positive regulation of peptidyl-tyrosine phosphorylation; • negative regulation of helicase activity; • protein tetramerization; • chromosome organization; • neuron apoptotic process; • positive regulation of thymocyte apoptotic process; • positive regulation of cell cycle arrest; • cellular response to hypoxia; • cellular response to ionizing radiation; • mitotic cell cycle arrest; • intrinsic apoptotic signaling pathway by p53 class mediator; • positive regulation of release of cytochrome c from mitochondria; • positive regulation of cell aging; • replicative senescence; • oxidative stress-induced premature senescence; • intrinsic apoptotic signaling pathway; • positive regulation of reactive oxygen species metabolic process; • positive regulation of intrinsic apoptotic signaling pathway;
	Sources: Amigo / QuickGO
RNA expression pattern
	More reference expression data
Orthologs
	This box: view; talk; edit;

Tumor protein p53
	; PDB rendering based on 1TUP: P53 complexed with DNA
Available structures
PDB	Ortholog search: PDBe, RCSB
PDBのIDコード一覧
	1A1U, 1AIE, 1C26, 1DT7, 1GZH, 1H26, 1HS5, 1JSP, 1KZY, 1MA3, 1OLG, 1OLH, 1PES, 1PET, 1SAE, 1SAF, 1SAK, 1SAL, 1TSR, 1TUP, 1UOL, 1XQH, 1YC5, 1YCQ, 1YCR, 1YCS, 2AC0, 2ADY, 2AHI, 2ATA, 2B3G, 2BIM, 2BIN, 2BIO, 2BIP, 2BIQ, 2FEJ, 2FOJ, 2FOO, 2GS0, 2H1L, 2H2D, 2H2F, 2H4F, 2H4H, 2H4J, 2H59, 2J0Z, 2J10, 2J11, 2J1W, 2J1X, 2J1Y, 2J1Z, 2J20, 2J21, 2K8F, 2L14, 2OCJ, 2PCX, 2QVQ, 2QXA, 2QXB, 2QXC, 2VUK, 2WGX, 2X0U, 2X0V, 2X0W, 2XWR, 2YBG, 2Z5S, 2Z5T, 3D05, 3D06, 3D07, 3D08, 3D09, 3D0A, 3DAB, 3DAC, 3IGK, 3IGL, 3KMD, 3KZ8, 3LW1, 3PDH, 3Q01, 3Q05, 3Q06, 3SAK, 3TG5, 3TS8, 4AGL, 4AGM, 4AGN, 4AGO, 4AGP, 4AGQ
識別記号
記号（英語版）	TP53; LFS1; P53; TRP53
その他ID	OMIM（英語版）: 191170 MGI（英語版）: 98834 HomoloGene（英語版）: 460 ChEMBL: 4096 GeneCards: TP53 Gene
遺伝子オントロジー
分子機能	• DNA strand annealing activity; • RNA polymerase II core promoter proximal region sequence-specific DNA binding transcription factor activity involved in positive regulation of transcription; • RNA polymerase II transcription factor binding; • protease binding; • p53 binding; • DNA binding; • chromatin binding; • damaged DNA binding; • sequence-specific DNA binding transcription factor activity; • copper ion binding; • protein binding; • ATP binding; • transcription factor binding; • zinc ion binding; • enzyme binding; • protein kinase binding; • ubiquitin protein ligase binding; • histone deacetylase regulator activity; • histone acetyltransferase binding; • identical protein binding; • transcription regulatory region DNA binding; • metal ion binding; • protein heterodimerization activity; • protein N-terminus binding; • chaperone binding; • protein phosphatase 2A binding; • MDM2 binding;
細胞の構成要素	• chromatin; • nuclear chromatin; • insoluble fraction; • nucleus; • nucleoplasm; • nucleoplasm; • replication fork; • transcription factor TFIID complex; • chromatin assembly complex; • nucleolus; • cytoplasm; • mitochondrion; • endoplasmic reticulum; • cytosol; • cytosol; • nuclear matrix; • nuclear body; • PML body; • protein complex;
生物学的プロセス	• protein import into nucleus, translocation; • cell cycle checkpoint; • negative regulation of transcription from RNA polymerase II promoter; • negative regulation of transcription from RNA polymerase II promoter; • negative regulation of transcription from RNA polymerase II promoter; • DNA strand renaturation; • in utero embryonic development; • somitogenesis; • T cell proliferation involved in immune response; • B cell lineage commitment; • T cell lineage commitment; • base-excision repair; • nucleotide-excision repair; • double-strand break repair; • regulation of transcription, DNA-dependent; • protein complex assembly; • apoptotic process; • apoptotic process; • response to DNA damage stimulus; • DNA damage response, signal transduction by p53 class mediator resulting in cell cycle arrest; • DNA damage response, signal transduction by p53 class mediator resulting in transcription of p21 class mediator; • ER overload response; • cell cycle arrest; • cell cycle arrest; • Ras protein signal transduction; • multicellular organismal development; • gastrulation; • negative regulation of neuroblast proliferation; • central nervous system development; • cell aging; • blood coagulation; • protein localization; • negative regulation of DNA replication; • cell proliferation; • negative regulation of cell proliferation; • determination of adult lifespan; • induction of apoptosis by intracellular signals; • rRNA transcription; • response to salt stress; • embryo development ending in birth or egg hatching; • response to X-ray; • response to gamma radiation; • cell differentiation; • negative regulation of cell growth; • DNA damage response, signal transduction by p53 class mediator; • DNA damage response, signal transduction by p53 class mediator; • negative regulation of transforming growth factor beta receptor signaling pathway; • positive regulation of histone deacetylation; • mitotic cell cycle G1/S transition DNA damage checkpoint; • positive regulation of protein oligomerization; • T cell differentiation in thymus; • cellular protein localization; • cellular response to UV; • multicellular organism growth; • cellular response to drug; • cellular response to glucose starvation; • DNA damage response, signal transduction by p53 class mediator resulting in induction of apoptosis; • regulation of apoptotic process; • positive regulation of apoptotic process; • negative regulation of apoptotic process; • negative regulation of apoptotic process; • positive regulation of neuron apoptosis; • interspecies interaction between organisms; • negative regulation of transcription, DNA-dependent; • positive regulation of transcription, DNA-dependent; • positive regulation of transcription, DNA-dependent; • positive regulation of transcription from RNA polymerase II promoter; • positive regulation of transcription from RNA polymerase II promoter; • response to antibiotic; • regulation of mitochondrial membrane permeability; • negative regulation of fibroblast proliferation; • positive regulation of peptidyl-tyrosine phosphorylation; • regulation of catalytic activity; • negative regulation of helicase activity; • protein tetramerization; • chromosome organization; • regulation of cell cycle; • positive regulation of thymocyte apoptosis; • positive regulation of cell cycle arrest; • cellular response to hypoxia; • cellular response to ionizing radiation; • signal transduction by p53 class mediator resulting in induction of apoptosis; • positive regulation of release of cytochrome c from mitochondria; • positive regulation of cell aging; • replicative senescence; • oxidative stress-induced premature senescence; • positive regulation of reactive oxygen species metabolic process; • positive regulation of intrinsic apoptotic signaling pathway;
	出典: Amigo / EGO
RNA発現パターン
	その他参照発現データ
オルソログ
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Wikipedia preview

出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2013/10/10 21:07:29」(JST)

wiki ja

[Wiki ja表示]

p53遺伝子（ピー53いでんし）とは、一つ一つの細胞内でDNA修復や細胞増殖停止、アポトーシスなどの細胞増殖サイクルの抑制を制御する機能を持ち、細胞ががん化したときアポトーシスを起させるとされる。この遺伝子による機能が不全となるとがんが起こると考えられている、いわゆる癌抑制遺伝子の一つ。

p53のpはタンパク質（protein）、53は分子量53,000を意味しタンパクは393個のアミノ酸から構成されている。この遺伝子は進化的に保存されており、昆虫や軟体動物にも存在している。ただしそれらのアミノ酸一次配列はかなり多様化している。またパラログとしてp63やp73もある。RB遺伝子とともによく知られている。

細胞が、がん化するためには複数の癌遺伝子と癌抑制遺伝子の変化が必要らしいことが分かっているが、p53遺伝子は悪性腫瘍（癌）において最も高頻度に異常が認められている。p53は、細胞の恒常性の維持やアポトーシス誘導といった重要な役割を持つことからゲノムの守護者（The Guardian of the genome）とも表現されるが、染色体構造が変化する機構と、それらの細胞内での働き、そしてそれらが生物にとってどのように大切なのかについてはよくわかっていない。

遺伝子座[編集]

ヒトのp53遺伝子は、第17番染色体短腕上（17p13.1）に存在する。

歴史[編集]

遺伝子産物であるp53は、1979年に腫瘍ウイルスSV40の大型T抗原と結合するタンパク質として発見された。その後の研究によりp53遺伝子が癌抑制遺伝子であることが証明され脚光を浴びることになった。

p53遺伝子は単に癌の抑制にのみ関与しているのではないことが示唆されている。2002年、Tynerらは通常のマウス（p53+/+）とp53が通常よりも活性化している変異マウス（p53+/m）を比較したところ、変異マウスでは癌の発生率は低かったものの組織の老化が早く寿命が短かったことを報告した^[2]。

機能[編集]

p53タンパク質は転写因子として働き、GADD45（英語版）、MDM2、p21CIP1/WAF1、BAX（英語版）、14-3-3δ（英語版）など多くの遺伝子群の発現に関与し多彩な生理機能を持つ。

損傷を受けたDNAの修復タンパク質の活性化
細胞周期の制御
DNAが修復不可能な損傷を受けた場合に、細胞の自殺であるアポトーシスを誘導

変異[編集]

半数以上の悪性腫瘍においてp53遺伝子の変異や欠失が認められる。変異の多くは点変異である。何らかの原因でp53遺伝子が損傷を受けると、細胞にアポトーシスが誘導されにくくなる。例えば、肺癌ではタバコに含まれるベンゾピレンという発癌物質によりp53遺伝子の変異が起こっている。また、肝細胞癌の原因の1つであるピーナッツに生えるカビが産生するアフラトキシンという物質は、p53遺伝子の249番目の塩基に点変異を多く引き起こす。

p53遺伝子の変異は抗p53抗体の出現と相関がみられる。日本では抗p53抗体測定は食道癌、大腸癌および乳癌が疑われる際に2007年11月より保険適応が認められた。

遺伝子治療[編集]

p53遺伝子の多彩な機能を利用して、癌の治療に応用しようとする試みがなされている。特によく研究がなされているのは、アデノウイルスなどのベクターを用いて癌細胞へp53遺伝子を導入する治療である。p53遺伝子に変異がある場合には、通常ではアポトーシスが起こるようなDNA障害が生じても細胞死が起こりにくい。このため、一般的にはp53遺伝子に変異を持つ癌では薬剤や放射線などの治療に抵抗性が存在する。遺伝子治療による癌細胞へのアポトーシスの誘導や、化学療法や放射線治療の効果の増強が期待されている。

Li-Fraumeni症候群[編集]

Li-Fraumeni症候群（リ・フラウメニ症候群）は家系内に脳腫瘍、乳癌、白血病や肉腫などの様々な癌が多発する稀な遺伝疾患である。p53遺伝子の欠損が原因で起こる。病名は発見者Frederick P. LiとJoseph F. Fraumeni, Jrに因む。

脚注[編集]

^ Cho Y, Gorina S, Jeffrey PD, Pavletich NP (1994). “Crystal structure of a p53 tumor suppressor-DNA complex: understanding tumorigenic mutations”. Science 265 (5170): 346-355. doi:10.1126/science.8023157. PMID 8023157.
^ Tyner SD, Venkatachalam S, Choi J, Jones S, Ghebranious N, Igelmann H, Lu X, Soron G, Cooper B, Brayton C, Park SH, Thompson T, Karsenty G, Bradley A, Donehower LA (2002). “p53 mutant mice that display early ageing-associated phenotypes”. Nature 415 (6867): 45-53. doi:10.1038/415045a. PMID 11780111.

外部リンク[編集]

ウィキメディア・コモンズには、P53遺伝子に関連するカテゴリがあります。

がん抑制遺伝子ｐ５３の新しい制御機構を発見(九州大学ホームページ)
The p53 web site

wiki en

[Wiki en表示]

For other uses, see P53 (disambiguation).

p53 (also known as protein 53 or tumor protein 53), is a tumor suppressor protein that in humans is encoded by the TP53 gene.^[2]^[3]^[4]^[5] p53 is crucial in multicellular organisms, where it regulates the cell cycle and, thus, functions as a tumor suppressor that is involved in preventing cancer. As such, p53 has been described as "the guardian of the genome" because of its role in conserving stability by preventing genome mutation.^[6]

The name p53 is in reference to its apparent molecular mass: It runs as a 53-kilodalton (kDa) protein on SDS-PAGE. But, based on calculations from its amino acid residues, p53's mass is actually only 43.7 kDa. This difference is due to the high number of proline residues in the protein, which slows its migration on SDS-PAGE, thus making it appear heavier than it actually is.^[7] This effect is observed with p53 from a variety of species, including humans, rodents, frogs, and fish.

Nomenclature[edit]

p53 is also known as:

UniProt name: Cellular tumor antigen p53
Antigen NY-CO-13
Phosphoprotein p53
Transformation-related protein 53 (TRP53)
Tumor suppressor p53

Gene[edit]

In humans, p53 is encoded by the TP53 gene located on the short arm of chromosome 17 (17p13.1).^[2]^[3]^[4]^[5] The gene spans 20 kb, with a non-coding exon 1 and a very long first intron of 10 kb.The coding sequence contains five regions showing a high degree of conservation in vertebrates, predominantly in exons 2, 5, 6, 7 and 8, but the sequences found in invertebrates show only distant resemblance to mammalian TP53.^[8] TP53 orthologs^[9] have been identified in most mammals for which complete genome data are available.

In humans, a common polymorphism involves the substitution of an arginine for a proline at codon position 72. Many studies have investigated a genetic link between this variation and cancer susceptibility, however, the results have been controversial. For instance, a meta-analysis from 2009 failed to show a link for cervical cancer.^[10] A 2011 study found that the TP53 proline mutation did have a profound effect on pancreatic cancer risk among males.^[11] A study of Arab women found that proline homozygosity at TP53 codon 72 is associated with a decreased risk for breast cancer.^[12] One study suggested that TP53 codon 72 polymorphisms, MDM2 SNP309, and A2164G may collectively be associated with non-oropharyngeal cancer susceptibility and that MDM2 SNP309 in combination with TP53 codon 72 may accelerate the development of non-oropharyngeal cancer in women.^[13] A 2011 study found that TP53 codon 72 polymorphism was associated with an increased risk of lung cancer.^[14]

Meta-analyses from 2011 found no significant associations between TP53 codon 72 polymorphisms and both colorectal cancer risk^[15] and endometrial cancer risk.^[16] A 2011 study of a Brazilian birth cohort found an association between the non mutant arginine TP53 and individuals without a family history of cancer.^[17] Another 2011 study found that the p53 homozygous (Pro/Pro) genotype was associated with a significantly increased risk for renal cell carcinoma.^[18]

(Italics are used to denote the TP53 gene name and distinguish it from the protein it encodes.)

Structure[edit]

Crystal structure of four p53 DNA binding domains (as found in the bioactive homo-tetramer) attached to the DNA binding site.

Human p53 is 393 amino acids long and has seven domains:

an acidic N-terminus transcription-activation domain (TAD), also known as activation domain 1 (AD1), which activates transcription factors: residues 1-42. The N-terminus contains two complementary transcriptional activation domains, with a major one at residues 1–42 and a minor one at residues 55–75, specifically involved in the regulation of several pro-apoptotic genes.^[19]
activation domain 2 (AD2) important for apoptotic activity: residues 43-63.
Proline rich domain important for the apoptotic activity of p53: residues 64-92.
central DNA-binding core domain (DBD). Contains one zinc atom and several arginine amino acids: residues 102-292. This region is responsible for binding the p53 co-repressor LMO3.^[20]
nuclear localization signaling domain, residues 316-325.
homo-oligomerisation domain (OD): residues 307-355. Tetramerization is essential for the activity of p53 in vivo.
C-terminal involved in downregulation of DNA binding of the central domain: residues 356-393.^[21]

A tandem of nine-amino-acid transactivation domains (9aaTAD) was identified in the AD1 and AD2 regions of transcription factor p53.^[22] KO mutations and position for p53 interaction with TFIID are listed below:^[23]

9aaTADs mediate p53 interaction with general coactivators - TAF9, CBP/p300 (all four domains KIX, TAZ1, TAZ2 and IBiD), GCN5 and PC4, regulatory protein MDM2 and replication protein A (RPA).^[24]^[25]

Mutations that deactivate p53 in cancer usually occur in the DBD. Most of these mutations destroy the ability of the protein to bind to its target DNA sequences, and thus prevents transcriptional activation of these genes. As such, mutations in the DBD are recessive loss-of-function mutations. Molecules of p53 with mutations in the OD dimerise with wild-type p53, and prevent them from activating transcription. Therefore OD mutations have a dominant negative effect on the function of p53. An example of a mutation in P53 is where arginine 248 is altered, sometimes causing a disruption in balance and making the protein unable to bind with the DNA.

Wild-type p53 is a labile protein, comprising folded and unstructured regions that function in a synergistic manner.^[26]

Function[edit]

p53 has many mechanisms of anticancer function, and plays a role in apoptosis, genomic stability, and inhibition of angiogenesis. In its anti-cancer role, p53 works through several mechanisms:

It can activate DNA repair proteins when DNA has sustained damage.
It can arrest growth by holding the cell cycle at the G₁/S regulation point on DNA damage recognition (if it holds the cell here for long enough, the DNA repair proteins will have time to fix the damage and the cell will be allowed to continue the cell cycle).
It can initiate apoptosis, the programmed cell death, if DNA damage proves to be irreparable.

p53 pathway: In a normal cell p53 is inactivated by its negative regulator, mdm2. Upon DNA damage or other stresses, various pathways will lead to the dissociation of the p53 and mdm2 complex. Once activated, p53 will induce a cell cycle arrest to allow either repair and survival of the cell or apoptosis to discard the damaged cell. How p53 makes this choice is currently unknown.

Activated p53 binds DNA and activates expression of several genes including microRNA miR-34a,^[27] WAF1/CIP1 encoding for p21 and hundreds of other down-stream genes. p21 (WAF1) binds to the G1-S/CDK (CDK2) and S/CDK complexes (molecules important for the G1/S transition in the cell cycle) inhibiting their activity.

When p21(WAF1) is complexed with CDK2 the cell cannot continue to the next stage of cell division. A mutant p53 will no longer bind DNA in an effective way, and, as a consequence, the p21 protein will not be available to act as the "stop signal" for cell division.^[28] Studies of human embryonic stem cells (hESCs) commonly describe the nonfunctional p53-p21 axis of the G1/S checkpoint pathway with subsequent relevance for cell cycle regulation and the DNA damage response (DDR). Importantly, p21 mRNA is clearly present and upregulated after the DDR in hESCs, but p21 protein is not detectable. In this cell type, p53 activates numerous microRNAs (like miR-302a, miR-302b, miR-302c, and miR-302d) that directly inhibit the p21 expression in hESCs.^[29]

Recent research has also linked the p53 and RB1 pathways, via p14ARF, raising the possibility that the pathways may regulate each other.^[30]

p53 by regulating LIF has been shown to facilitate implantation in the mouse model and possibly in humans.^[31]

p53 expression can be stimulated by UV light, which also causes DNA damage. In this case, p53 can initiate events leading to tanning.^[32]^[33]

Regulation[edit]

p53 becomes activated in response to myriad stressors, including but not limited to DNA damage (induced by either UV, IR, or chemical agents such as hydrogen peroxide), oxidative stress,^[34] osmotic shock, ribonucleotide depletion, and deregulated oncogene expression. This activation is marked by two major events. First, the half-life of the p53 protein is increased drastically, leading to a quick accumulation of p53 in stressed cells. Second, a conformational change forces p53 to be activated as a transcription regulator in these cells. The critical event leading to the activation of p53 is the phosphorylation of its N-terminal domain. The N-terminal transcriptional activation domain contains a large number of phosphorylation sites and can be considered as the primary target for protein kinases transducing stress signals.

The protein kinases that are known to target this transcriptional activation domain of p53 can be roughly divided into two groups. A first group of protein kinases belongs to the MAPK family (JNK1-3, ERK1-2, p38 MAPK), which is known to respond to several types of stress, such as membrane damage, oxidative stress, osmotic shock, heat shock, etc. A second group of protein kinases (ATR, ATM, CHK1 and CHK2, DNA-PK, CAK, TP53RK) is implicated in the genome integrity checkpoint, a molecular cascade that detects and responds to several forms of DNA damage caused by genotoxic stress. Oncogenes also stimulate p53 activation, mediated by the protein p14ARF.

In unstressed cells, p53 levels are kept low through a continuous degradation of p53. A protein called Mdm2 (also called HDM2 in humans), which is itself a product of p53, binds to p53, preventing its action and transports it from the nucleus to the cytosol. Also Mdm2 acts as ubiquitin ligase and covalently attaches ubiquitin to p53 and thus marks p53 for degradation by the proteasome. However, ubiquitylation of p53 is reversible.

A ubiquitin specific protease, USP7 (or HAUSP), can cleave ubiquitin off p53, thereby protecting it from proteasome-dependent degradation. This is one means by which p53 is stabilized in response to oncogenic insults. USP42 has also been shown to deubiquitinate p53 and may be required for the ability of p53 to respond to stress.^[35]

Recent research has shown that HAUSP is mainly localized in the nucleus, though a fraction of it can be found in the cytoplasm and mitochondria. Overexpression of HAUSP results in p53 stabilization. However, depletion of HAUSP does not result to a decrease in p53 levels but rather increases p53 levels due to the fact that HAUSP binds and deubiquitinates Mdm2. It has been shown that HAUSP is a better binding partner to Mdm2 than p53 in unstressed cells.

USP10 however has been shown to be located in the cytoplasm in unstressed cells and deubiquitinates cyptoplasmic p53, reversing Mdm2 ubiquitination. Following DNA damage, USP10 translocates to the nucleus and contributes to p53 stability. Also USP10 does not interact with Mdm2.^[36]

Phosphorylation of the N-terminal end of p53 by the above-mentioned protein kinases disrupts Mdm2-binding. Other proteins, such as Pin1, are then recruited to p53 and induce a conformational change in p53, which prevents Mdm2-binding even more. Phosphorylation also allows for binding of transcriptional coactivators, like p300 and PCAF, which then acetylate the carboxy-terminal end of p53, exposing the DNA binding domain of p53, allowing it to activate or repress specific genes. Deacetylase enzymes, such as Sirt1 and Sirt7, can deacetylate p53, leading to an inhibition of apoptosis.^[37] Some oncogenes can also stimulate the transcription of proteins that bind to MDM2 and inhibit its activity.

Role in disease[edit]

Overview of signal transduction pathways involved in apoptosis.

A micrograph showing cells with abnormal p53 expression (brown) in a brain tumour. p53 immunostain.

If the TP53 gene is damaged, tumor suppression is severely reduced. People who inherit only one functional copy of the TP53 gene will most likely develop tumors in early adulthood, a disorder known as Li-Fraumeni syndrome. The TP53 gene can also be damaged in cells by mutagens (chemicals, radiation, or viruses), increasing the likelihood that the cell will begin decontrolled division. More than 50 percent of human tumors contain a mutation or deletion of the TP53 gene.^[38] Increasing the amount of p53, which may initially seem a good way to treat tumors or prevent them from spreading, is in actuality not a usable method of treatment, since it can cause premature aging.^[39] However, restoring endogenous p53 function holds a lot of promise. Research has been done to show that this restoration can lead to regression of certain cancer cells without damaging other cells in the process. The ways in which tumor regression occur depends chiefly on tumor type. With restoration of endogenous p53 function, lymphomas exhibit apoptosis and cell growth is lowered to normal levels. Thus, pharmacological reactivation of p53 presents itself as a viable cancer treatment option.^[40]^[41] Loss of p53 creates genomic instability that most often results in the aneuploidy phenotype.^[42]

Certain pathogens can also affect the p53 protein that the TP53 gene expresses. One such example, human papillomavirus (HPV), encodes a protein, E6, which binds to the p53 protein and inactivates it. This, in synergy with the inactivation of another cell cycle regulator, pRb, by the HPV protein E7, allows for repeated cell division manifested in the clinical disease of warts. Certain HPV types, in particular types 16 and 18, can also lead to progression from a benign wart to low or high-grade cervical dysplasia, which are reversible forms of precancerous lesions. Persistent infection of the cervix over the years can cause irreversible changes leading to carcinoma in situ and eventually invasive cervical cancer. This results from the effects of HPV genes, particularly those encoding E6 and E7, which are the two viral oncoproteins that are preferentially retained and expressed in cervical cancers by integration of the viral DNA into the host genome.^[43]

In healthy humans, the p53 protein is continually produced and degraded in the cell. The degradation of the p53 protein is, as mentioned, associated with MDM2 binding. In a negative feedback loop, MDM2 is itself induced by the p53 protein. However, mutant p53 proteins often do not induce MDM2, and are thus able to accumulate at very high concentrations. Worse, mutant p53 protein itself can inhibit normal p53 protein levels. In some cases, single missense mutations in p53 have been shown to disrupt p53 stability and function.^[44]

Experimental analysis of p53 mutations[edit]

Most p53 mutations are detected by DNA sequencing. However, it is known that single missense mutations can have a large spectrum from rather mild to very severe functional effects.^[44]

Discovery[edit]

p53 was identified in 1979 by Lionel Crawford, David P. Lane, Arnold Levine, and Lloyd Old, working at Imperial Cancer Research Fund (UK) Princeton University/UMDNJ (Cancer Institute of New Jersey), and Memorial Sloan-Kettering Cancer Center, respectively. It had been hypothesized to exist before as the target of the SV40 virus, a strain that induced development of tumors. The TP53 gene from the mouse was first cloned by Peter Chumakov of the Russian Academy of Sciences in 1982,^[45] and independently in 1983 by Moshe Oren in collaboration with David Givol (Weizmann Institute of Science).^[46]^[47] The human TP53 gene was cloned in 1984^[2] and the full length clone in 1985.^[48]

It was initially presumed to be an oncogene due to the use of mutated cDNA following purification of tumour cell mRNA. Its character as a tumor suppressor gene was finally revealed in 1989 by Bert Vogelstein working at Johns Hopkins School of Medicine.^[49]

Warren Maltzman, of the Waksman Institute of Rutgers University first demonstrated that TP53 was responsive to DNA damage in the form of ultraviolet radiation.^[50] In a series of publications in 1991-92, Michael Kastan, Johns Hopkins University, reported that TP53 was a critical part of a signal transduction pathway that helped cells respond to DNA damage.^[51]

In 1992, Wafik El-Deiry when he was working with Bert Vogelstein at Johns Hopkins University identified the consensus sequence, to which human p53 could bind, by immunoprecipitating human genomic DNA that could be bound by baculovirus-produced human p53 protein. This sequence was published in the first issue of the journal Nature Genetics in 1992 in work that is highly cited. The consensus sequence is 5'-RRRCWWGYYY-N(0-13)-RRRCWWGYYY-3' and is located in the regulatory regions of genes that are activated by the p53 transcription factor. The presence of p53 response elements in or around genes (promoters, upstream sequences, introns) is a powerful predictor of regulation and activation of a particular gene by p53.

In 1993, p53 was voted molecule of the year by Science magazine.^[52]

That same year, 1993, Wafik El-Deiry when he was working with Bert Vogelstein at Johns Hopkins University discovered p21(WAF1) as a gene regulated directly by p53. This work was reported in the most highly cited paper ever published in the journal Cell, and provided a molecular mechanism by which mammalian cells undergo growth arrest when damaged. The p21(WAF1) protein binds directly to cyclin-CDK complexes that drive forward the cell cycle and inhibits their kinase activity thereby causing cell cycle arrest to allow repair to take place. p21 can also mediate growth arrest associated with differentiation and a more permanent growth arrest associated with cellular senescence. The p21 gene contains several p53 response elements that mediate direct binding of the p53 protein, resulting in transcriptional activation of the gene encoding the p21(WAF1) protein.

Interactions[edit]

p53 has been shown to interact with:

AIMP2,^[53]
ANKRD2,^[54]
APTX,^[55]
ATM,^[56]^[57]^[58]^[59]^[60]
ATR,^[56]^[57]
ATF3,^[61]^[62]
AURKA,^[63]
BAK1,^[64]
BARD1,^[65]
BLM,^[66]^[67]^[68]^[69]
BRCA1,^[65]^[70]^[71]^[72]^[73]
BRCA2,^[65]^[74]
BRCC3,^[65]
BRE,^[65]
CEBPZ,^[75]
CDC14A,^[76]
Cdk1,^[77]^[78]
CFLAR,^[79]
CHEK1,^[66]^[80]^[81]
CCNG1,^[82]
CREBBP,^[83]^[84]^[85]
CREB1,^[85]
Cyclin H,^[86]
CDK7,^[86]^[87]
DNA-PKcs,^[57]^[80]^[88]
E4F1,^[89]^[90]
EFEMP2,^[91]
EIF2AK2,^[92]
ELL,^[93]
EP300,^[84]^[94]^[95]^[96]
ERCC6,^[97]^[98]
GNL3,^[99]
GPS2,^[100]
GSK3B,^[101]
HSP90AA1,^[102]^[103]^[104]
HIF1A,^[105]^[106]^[107]^[108]
HIPK1,^[109]
HIPK2,^[110]^[111]
HMGB1,^[112]^[113]
HSPA9,^[114]
Huntingtin,^[115]
ING1,^[116]^[117]
ING4,^[118]^[119]
ING5,^[118]
IκBα,^[120]
KPNB1,^[102]
LMO3,^[20]
Mdm2,^[83]^[121]^[122]^[123]
MDM4,^[124]^[125]
MED1,^[126]^[127]
MAPK9,^[128]^[129]
MNAT1,^[87]
NDN,^[130]
NCL,^[131]
NUMB,^[132]
NF-κB,^[133]
P16,^[89]^[123]^[134]
PARC,^[135]
PARP1,^[55]^[136]
PIAS1,^[91]^[137]
CDC14B,^[76]
PIN1,^[138]^[139]
PLAGL1,^[140]
PLK3,^[141]^[142]
PRKRA,^[143]
PHB,^[144]
PML,^[121]^[145]^[146]
PSME3,^[147]
PTEN,^[122]
PTK2,^[148]
PTTG1,^[149]
RAD51,^[65]^[150]^[151]
RCHY1,^[152]^[153]
RELA,^[133]
RPA1,^[154]^[155]
RPL11,^[134]
S100B,^[156]
SUMO1,^[157]^[158]
SMARCA4,^[159]
SMARCB1,^[159]
SMN1,^[160]
STAT3,^[133]
TBP,^[161]^[162]
TFAP2A,^[163]
TFDP1,^[164]
TIGAR,^[165]
TOP1,^[166]^[167]
TOP2A,^[168]
TP53BP1,^[66]^[169]^[170]^[171]^[172]^[173]^[174]
TP53BP2,^[174]^[175]
TOP2B,^[168]
TP53INP1,^[176]^[177]
TSG101,^[178]
UBE2A,^[179]
UBE2I,^[91]^[157]^[180]^[181]
UBC,^[53]^[147]^[158]^[182]^[183]^[184]^[185]^[186]
USP7,^[187]
WRN,^[69]^[188]
WWOX,^[189]
XPB,^[97]
YBX1,^[54]^[190]
YPEL3,^[191]
YWHAZ,^[192]
Zif268,^[193]
ZNF148,^[194]

Interactive pathway map[edit]

Click on genes, proteins and metabolites below to link to respective articles. ^{[§ 1]}

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Fluorouracil (5-FU) Activity edit

^ The interactive pathway map can be edited at WikiPathways: "FluoropyrimidineActivity_WP1601".

References[edit]

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External links[edit]

Wikimedia Commons has media related to Tumor suppressor protein p53.

Lane Group at the Institute of Molecular and Cell Biology (IMCB), Singapore. p53 Knowledgebase [Retrieved 2008-04-06].
GeneReviews/NCBI/NIH/UW entry on Li-Fraumeni Syndrome
TUMOR PROTEIN p53 @ OMIM
[3] p53 restoration of function
p53 @ The Atlas of Genetics and Cytogenetics in Oncology and Haematology
TP53 Gene @ GeneCards
p53 News provided by insciences organisation
David S. Goodsell. RCSB Protein Data Bank. p53 Tumor Suppressor; 2002-07-01 [Retrieved 2008-04-06].
Thierry Soussi. p53 Web Site [Retrieved 2008-04-06].
The George Pantziarka TP53 Trust A support group from the UK for sufferers of Li-Fraumeni Syndrome or other TP53-related disorders
IARC TP53 Somatic Mutations database maintained at IARC, Lyon, by Magali Olivier

UpToDate Contents

全文を閲覧するには購読必要です。 To read the full text you will need to subscribe.

1. リ・フラウメニ症候群 li fraumeni syndrome
2. びまん性大細胞型B細胞性リンパ腫および原発性縦隔大細胞型B細胞リンパ腫の病理学 pathobiology of diffuse large b cell lymphoma and primary mediastinal large b cell lymphoma
3. 大腸癌の分子遺伝学 molecular genetics of colorectal cancer
4. 限局性初期乳癌における予後予測因子 prognostic and predictive factors in early non metastatic breast cancer
5. 子宮体癌：病理組織学および病因 endometrial carcinoma histopathology and pathogenesis

English Journal

Induction of apoptosis in non-small cell lung cancer by downregulation of MDM2 using pH-responsive PMPC-b-PDPA/siRNA complex nanoparticles.

Yu H, Zou Y, Jiang L, Yin Q, He X, Chen L, Zhang Z, Gu W, Li Y.SourceCenter of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai 201203, China.
Biomaterials.Biomaterials.2013 Apr;34(11):2738-47. doi: 10.1016/j.biomaterials.2012.12.042. Epub 2013 Jan 24.
Non-small cell lung cancer (NSCLC) accounts for the majority of lung cancer caused human death. In this work, we selected oncogene mouse double minute 2 (MDM2) as a therapeutic target for NSCLC treatment and proposed that sufficient MDM2 knockdown could inhibit tumor growth via induction of cell cyc
PMID 23352573

Mdm2 antagonists induce apoptosis and synergize with cisplatin overcoming chemoresistance in TP53 wild-type ovarian cancer cells.

Mir R, Tortosa A, Martinez-Soler F, Vidal A, Condom E, Pérez-Perarnau A, Ruiz-Larroya T, Gil J, Giménez-Bonafé P.SourceDepartament de Ciències Fisiològiques II, Faculty of Medicine, Campus of Health Sciences of Bellvitge, Universitat de Barcelona, IDIBELL, Spain.
International journal of cancer. Journal international du cancer.Int J Cancer.2013 Apr 1;132(7):1525-36. doi: 10.1002/ijc.27832. Epub 2012 Oct 11.
Ovarian cancer (OVCa) is the leading cause of death from gynecological malignancies. Although treatment for advanced OVCa has improved with the introduction of taxane-platinum chemotherapy, the majority of patients will develop resistance to the treatment, leading to poor prognosis. One of the cause
PMID 22961628

Addition of interferon-α to the p53-SLP® vaccine results in increased production of interferon-γ in vaccinated colorectal cancer patients: A phase I/II clinical trial.

Zeestraten EC, Speetjens FM, Welters MJ, Saadatmand S, Stynenbosch LF, Jongen R, Kapiteijn E, Gelderblom H, Nijman HW, Valentijn AR, Oostendorp J, Fathers LM, Drijfhout JW, van de Velde CJ, Kuppen PJ, van der Burg SH, Melief CJ.SourceDepartment of Surgery, Leiden University Medical Center, Leiden, The Netherlands.
International journal of cancer. Journal international du cancer.Int J Cancer.2013 Apr 1;132(7):1581-91. doi: 10.1002/ijc.27819. Epub 2012 Nov 21.
We previously established safety and immunogenicity of a p53 synthetic long peptides (p53-SLP®) vaccine. In the current trial, we investigated whether combination of interferon-alpha (IFN-α) with p53-SLP® is both safe and able to improve the induced p53-specific IFN-γ response. Eleven colorectal
PMID 22948952

p53 regulates epithelial-mesenchymal transition induced by transforming growth factor β.

Termén S, Tan EJ, Heldin CH, Moustakas A.SourceLudwig Institute for Cancer Research, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
Journal of cellular physiology.J Cell Physiol.2013 Apr;228(4):801-13. doi: 10.1002/jcp.24229.
Epithelial plasticity characterizes embryonic development and diseases such as cancer. Epithelial-mesenchymal transition (EMT) is a reversible and guided process of plasticity whereby embryonic or adult epithelia acquire mesenchymal properties. Multiple signaling pathways control EMT, and the transf
PMID 23018556

Japanese Journal

A more efficient method to generate integration-free human iPS cells.

Okita Keisuke,Matsumura Yasuko,Sato Yoshiko,Okada Aki,Morizane Asuka,Okamoto Satoshi,Hong Hyenjong,Nakagawa Masato,Tanabe Koji,Tezuka Ken-Ichi,Shibata Toshiyuki,Kunisada Takahiro,Takahashi Masayo,Takahashi Jun,Saji Hiroh,Yamanaka Shinya
Nature methods, 2011-04-03
… 2011-04-05.We report a simple method, using p53 suppression and nontransforming L-Myc, to generate human induced pluripotent stem cells (iPSCs) with episomal plasmid vectors. …
NAID 120002949763

LBH589, a deacetylase inhibitor, induces apoptosis in adult T-cell leukemia/lymphoma cells via activation of a novel RAIDD-caspase-2 pathway.

Hasegawa H,Yamada Yasuaki,Tsukasaki Katsumi,Mori N,Tsuruda Kazuto,Sasaki Daisuke,Usui Tetsuya,Osaka Akemi,Atogami Sunao,Ishikawa Chie,Machijima Yoshiaki,Sawada S,Hayashi Tomayoshi,Miyazaki Yasushi,Kamihira Shimera
Leukemia : official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 25(4), 575-578, 2011-04
… Analyses, including with a DNA microarray, revealed that neither death receptors nor p53 pathways contributed to the apoptosis. … Furthermore, small interfering RNA experiments targeting caspase-2, caspase-9, RAIDD, p53-induced protein with a death domain (PIDD) and RIPK1 (RIP) indicated that activation of RAIDD is crucial and an event initiating this pathway. …
NAID 120002835134

幽門輪温存膵頭十二指腸切除術(PPPD)後の残胃の癌発生に関する臨床病理組織学的検討

古川健司,西川俊郎,桂川秀雄,山本雅一
東京女子医科大学雑誌 81(1), 13-22, 2011-02-25
… [対象と方法]:1984年から2003年までに経験したPPPD後の胃癌4例を対象に、発生母地粘膜の萎縮、ピロリ菌の有無、TFF2陽性細胞の有無、p53蛋白の発現、DGRに関しては、DGRが原因で発癌する場合、高率に認められるgastritis cystic polyposa(GCP)の有無について検討した。 … また、萎縮粘膜内でp53蛋白の発現が認められたが、GCPは、1例も認められなかった。 …
NAID 110008426932

Related Pictures

★リンクテーブル★

国試過去問	「098G055」「105G032」
リンク元	「子宮体癌」「胆嚢癌」「膠芽腫」「癌抑制遺伝子」
拡張検索	「protein p53」
関連記事	「p」

「098G055」

　　[★]

誤っている組合せはどれか。

a. アミロイドの沈着－老化徴候
b. 一酸化窒素の上昇－血管拡張
c. LDLコレステロールの高値－動脈硬化
d. テロメア長の短縮－細胞分裂停止
e. p53遺伝子の不活化－癌化抑制

[正答]

※国試ナビ4※　［098G054］←［国試_098］→［098G056］

「105G032」

　　[★]

機能の不活性化がヒトでの発癌につながる遺伝子はどれか。 2つ選べ。

a　c-myc(MYC)
b　erbB2(ERBB2)
c　K-ras(KRAS)
d　p53(TP53)
e　Rb(RB)

[正答]

※国試ナビ4※　［105G031］←［国試_105］→［105G033］

「子宮体癌」

　　[★]

英: uterine corpus cancer, carcinoma of uterine corpus, cancer of the uterine body
ラ: carcinoma corporis uteri
同: 子宮内膜癌 endometrial carcinoma endometrial cancer
関: 子宮、腫瘍、産婦人科学、子宮内膜増殖症(前癌病変)

G9M.157(進行期分類)

定義

子宮体部内膜に発生する上皮性悪性腫瘍。

疫学

発生頻度は欧米に多く、日本では少ない(女性人口10万当たり4)→高齢化、生活習慣との関連
発症年齢は50歳代が最も多く、閉経後が7割を占める。40歳以下の婦人は5%程度。
妊娠中および分娩後5年以内に体癌が発見されることはほとんどない。
日本では近年増加傾向。子宮癌全体の30%を占める(みえる9.150)

リスクファクター

プロゲステロンに拮抗されずに、エストロゲンに長期暴露されることによる

典型像：60歳くらいの太った未産の女性
未婚、不妊、閉経後、高い初婚・初妊年齢、少ない妊娠・出産回数、卵胞ホルモン服用歴、肥満
卵巣機能異常(無排卵周期症、PCOSなどの既往)　→　正常量のエストロゲンが存在するものの、これに拮抗するプロゲステロンが欠乏する

出典不明

未経産、肥満、高血圧、糖尿病、家族歴(HNPCC等)、エストロゲン製剤の使用、顆粒膜細胞腫・莢膜細胞腫、PCOS

症状

ほとんどの場合に症状がある。
9割で不正性器出血がみられる。そのほか過多月経、異常帯下、下腹部痛など。

子宮体癌の組織的分類

()内の頻度はG9M.155

子宮内膜癌

腺癌：ほとんどが腺癌

類内膜癌(80-90%)：正常子宮内膜腺に類似。充実性増殖の割合によりgrade1～grade3に分類される。
漿液性腺癌(1-10%)：乳頭状に入り組む。砂粒小体
明細胞腺癌(1-6.6%)：明細胞、ホブネイル細胞
粘液性腺癌(1%以下)：

扁平上皮癌
混合癌
未分化癌

G9M.155

腺癌(95%以上)

類内膜癌(80-90%)　→　類内膜腺癌(60-70%)、扁平上皮への分化を伴う類内膜腺癌(20-30%)

細胞異型が強い場合にはGradeを上げる。

Grade1(高分化型)充実増殖の占める割合が腺癌成分の5%以下。プロゲステロン受容体陽性率高。予後良好
Grade2(中分化型)充実増殖の占める割合が腺癌成分の6-50%。プロゲステロン受容体陽性率中。予後中等度
Grade3(低分化型)充実増殖の占める割合が腺癌成分の50%超。プロゲステロン受容体陽性率低。予後不良

その他(扁平上皮癌など(5%以下))

発生機序による分類

type I：エストロゲン依存性。発症は遺伝子変異とエストロゲンの長期持続刺激による子宮内膜細胞の異常増殖

若年者の子宮体癌は多嚢胞性卵巣に由来するものがある

type II：エストロゲン非依存性。子宮内膜異型増殖症を介さないで癌化する

	I型子宮体癌	II型子宮体癌
発生機序	エストロゲンへの長期暴露	de novo癌
好発年齢	閉経前-閉経早期
頻度	80-90%	10-20%
病巣周辺の子宮内膜異型増殖症	あり	なし
組織型	類内膜腺癌	漿液性腺癌明細胞腺癌
分化度	高分化型	低分化型
筋層浸潤	軽度	高度
予後	比較的良好	不良
遺伝子変異	K-ras, PTEN	p53

検査

超音波エコー(経膣超音波)

子宮内膜の肥厚が認められる。

腫瘍マーカー

進行例でCA125、CA19-9の上昇

MRI

T2画像が有用。
junctional zoneの菲薄化・欠損
子宮内膜＞腫瘍＞筋層＞junctional zone

診断

スクリーニング：細胞診

子宮腔内の吸引あるいは擦過細胞診による検出率：90%以上
子宮頚・腟部からの細胞採取による検出率：50%以下

確定診断：子宮内膜の試験掻爬組織診

手術進行期分類 (日産婦 1995,FIGO1998)

原則として手術進行期分類を用い、手術を行っていない例では臨床進行期分類を用いる

体　→　頚　→　骨盤内　→　骨盤外

0期：　子宮内膜異型増殖症

I期：　子宮体部に限局

Ia期：　子宮内膜に限局

Ib期：　浸潤が子宮筋層1/2以内

Ic期：　浸潤が子宮筋層1/2を越える

II期：　子宮頸部に及ぶ

IIa期：　頸管腺のみ

IIb期：　頸部間質浸潤

III期：　子宮外に広がるが小骨盤腔を越えない、または所属リンパ節転移

IIIa期：　漿膜浸潤、付属器浸潤、腹膜細胞診陽性

IIIb期：　膣転移

IIIc期：　所属リンパ節転移(骨盤リンパ節、傍大動脈リンパ節)

IV期：　小骨盤腔を越える、または明らかな膀胱または腸粘膜を侵す

IVa期：　膀胱、腸粘膜へ浸潤

IVb期：　遠隔転移（腹腔内リンパ節、鼠径リンパ節転移を含む）

転移

直接浸潤
リンパ行性転移

症状

不正性器出血、腹痛

治療

手術療法、放射線療法、薬物療法(抗ガン剤、ホルモン療法)
治療法の基本は手術療法(単純子宮全摘術、準広汎子宮全摘術、広汎子宮全摘術)。

補助的に摘出術を追加することがある：両側付属器切除術、リンパ節郭清、部分大網切除術

薬物療法・放射線療法：手術不能例、再発例、術後の補助療法

薬物療法

抗悪性腫瘍薬

シスプラチン、アドリアマイシン、タキサン系の多剤併用療法

化学療法のレジメン

参考：http://medical.nikkeibp.co.jp/leaf/all/nmk/cr/report/200702/502818.htm

世界ではアドリアマイシン単剤療法(A)に対してアドリアマイシンとシスプラチンの併用療法(AP)の治療効果、あるいはアドリアマイシンとシスプラチンの併用療法(AP)に対してアドリアマイシン、シスプラチン、およびパクリタキセルの三剤併用療法(TAP)の治療効果を比較した臨床研究がなされている。それぞれの後者の方が奏効率が高い。しかし、TAP 療法は毒性が高く、子宮体癌に対する標準治療としては2006年の段階で認められていない。
現在は卵巣癌の標準化学療法として知られているパクリタキセルとカルボプラチンの併用療法は、子宮体癌に対しても奏効率が非常に高く、標準化学療法としての期待が高まっている。
GOG(the gynecologic oncology group)ではTC療法とTAP療法を直接比較する試験を進行させている。結果が出るまでには数年かかる。

ガイドライン的には「アンスラサイクリン系とプラチナ製剤を含む薬剤の選択が薦められている(グレードB)。タキサン系製剤も併用さているが、その十分な根拠は得られていない(グレードC)。(子宮体癌の治療ガイドライン2006年)

一般的な抗腫瘍薬による副作用

自覚症状：悪心・嘔吐、食欲不振、全身倦怠感、筋肉痛、脱毛、手足のしびれ。
検査値：血液中の白血球、血小板、血色素の減少→感染症に対する抵抗力の低下。

ホルモン療法

ホルモン療法単体：挙児希望のGrade1のIa期：高用量MPA
術後補助療法：再発リスクの低い場合、高用量黄体ホルモン療法は非推奨(グレードD)(参考2)

手術療法

1. 子宮摘出術

単純子宮全摘術

子宮体部に限局しているとき

準広汎子宮全摘術

子宮体部に限局しているとき

広汎子宮全摘術

MRIや肉眼で明らかな頸部間質浸潤が認められるとき。

2. 両側付属器切除術
3. リンパ節郭清

骨盤リンパ節郭清：基本的に施行。省略するのは、類内膜癌Grade1で、画像診断で病変が子宮内膜に限局すると推定される場合のみ。
傍大動脈リンパ節郭清
鼠径リンパ節郭清

4. 部分大網切除術

傍大動脈リンパ節郭清術と部分大網切除術の適応

転移リスクが高いため

1. 骨盤リンパ節転移例
2. 付属器転移例
3. 筋層浸潤が1/2を超す例
4. 予後不良例(組織型が類内膜癌Grade3、漿液性腺癌、明細胞腺癌、癌肉腫など)。太字の物は特に大網転移率が高い。

放射線療法

子宮頚癌(扁平上皮癌)より放射線は有効ではない。　→　放射線療法は腺癌に奏効しづらい！！！

子宮温存を希望する若年性子宮体癌

根治治療ではなく、いずれは子宮全摘が必要。
再発例では子宮全摘

適応

画像診断上Ia期(内膜限局)
G1の類内膜腺癌

治療

子宮内膜全面掻爬
高用量黄体ホルモン療法

予後

予後規定因子

筋層浸潤の深さ、頚部浸潤、子宮外進展、リンパ節転移、病理組織型、組織学的分化度、血管・リンパ管侵襲

5年生存率

臨床進行期	5年生存率(%)
臨床進行期	出典不明(相対)	NGY.229
I	86	79
II	68	66.8
III	42	37.5
IV	16	8.5

国試

104B035

症例

55歳の女性。不正性器出血を主訴に来院した。未経妊、閉経51歳。不妊治療をした経験がある。子宮は鶏卵大で卵巣は両側とも触知しない。経膣超音波で子宮内膜の肥厚が見られる。

子宮体癌治療ガイドライン(2006年)

FIGOは子宮体癌の手術進行期分類を採用。

1)進行期決定のために手術術式の選択が必要である。
2)子宮体癌は放射線感受性が低く、抗ガン剤の標準治療の確立が遅れている。

このことから子宮体癌では手術療法が第一選択。高齢や内科的合併症などの理由で、放射線療法が選択される場合もある。

参考

1.

http://tyama7.blog.ocn.ne.jp/obgyn/2006/10/post_d2b6.html

2. 子宮体がん治療ガイドライン2009年版：（金原出版）

http://www.jsgo.gr.jp/guideline/taigan.html

3. ガイドライン

http://minds.jcqhc.or.jp/stc/0050/1/0050_G0000135_GL.html

「胆嚢癌」

　　[★]

英: gallbladder cancer, carcinoma of the gallbladder
関: 胆道癌、胆管癌

疫学

高齢者女性。
60歳代。男女比=1：2

リスクファクター(ガイドラインより)

1. 膵・胆管合流異常

胆管拡張をともなわない膵・胆管合流異常は胆嚢癌のハイリスクファクターである。
膵・胆管合流異常の胆嚢において粘膜過形成，K-ras遺伝子変異，p53蛋白過剰発現が高頻度に認められる

2. 胆嚢腺腫

胆嚢癌の発生母地病変として腺腫や異型上皮，腸上皮化生が関与する可能性が報告されている
胆嚢ポリープが10mm以上で，かつ増大傾向を認める場合，または大きさにかかわらず広基性病変では胆嚢癌の頻度が高いと考えられる。

不明

1. 胆嚢結石症，陶器様胆嚢

現時点では胆嚢結石と胆嚢癌との直接的因果関係は証明されておらず，無症候性胆嚢結石の場合，長期間経過観察しても胆嚢癌が発生する危険は少ないといえる。
胆嚢壁の石灰化や陶器様胆嚢と胆嚢癌との因果関係は現段階では統一見解がない。

2. 胆嚢腺筋腫症

現時点で胆嚢腺筋腫症が胆嚢癌のリスクファクターであるか否かの結論は得られていない。

早期癌

早期胆嚢癌：組織学的深達度が粘膜(m)・固有筋層(mp)にとどまるもの。リンパ節転移の有無は問わない。癌の先端部がRokitansky-Aschoff sinusに限局していれば、深達度に寄らず粘膜内癌 (YN.B-74)

症状

初期には無症状
腹痛(72%)、黄疸(58%)、体重減少(47%)

黄疸が出現した頃にはかなり進行している

検査

CT

[show details]

予後

早期癌：op後の累積5年生存率は80%。
進行癌：漿膜下層限局で5年生存率は50%。漿膜波及で10%。

ガイドライン

http://minds.jcqhc.or.jp/stc/0058/1/0058_G0000159_GL.html

国試

103D020

「膠芽腫」

　　[★]

英: glioblastoma
同: 神経膠芽腫、多形膠芽腫 glioblastoma multiforme; グリア芽細胞腫、グリア芽腫、膠芽細胞腫、グリオブラストーマ、膠芽腫、神経膠芽細胞腫
関: 脳腫瘍、星状細胞腫

神経系 091009IV

分類

原発性脳腫瘍

神経膠腫 glioma

星状細胞腫 astrocytoma

膠芽腫 glioblastoma

概念

肉眼的・組織的に多彩な形態を示すので多形膠芽腫とも呼ばれる(SCN.170)

病因

primary dlioblastoma：genetic defects(EGFR amplification, MDM2 overexpression, p16 deletion, PTEN mutation)：older patients
secondary glioblastoma：p53 tumor suppressor gene inactivating → PDGF-A amplification：young patiens

病理

壊死、出血、嚢胞形成 (SCN.170)
大小様々の円型、紡錘型、不整型の細胞が密に増殖 (SCN.170)
腫瘍内の様々な壊死。壊死周囲に核が柵状に配列する所見(nuclear pseudopalisading, pseudopalisading necrosis)、血管の増殖、内皮細胞の増殖(SCN.170)

pseudopalisading necrosisは膠芽腫に特徴的(palisade:柵)

治療

手術療法 + 放射線療法&化学療法

参考

1. MRI画像

http://square.umin.ac.jp/sawamura/braintumors/astrocytictumor.html

「癌抑制遺伝子」

　　[★]

英: tumor suppressor gene, tumor suppressor genes, suppressor oncogene, anti-oncogene
同: がん抑制遺伝子、腫瘍抑制遺伝子
関: 癌遺伝子

表：LAB.1222
APC、BRCA1、BRCA2、DCC、NF1、NF2、p16、p53、PTEN、Rb、VHL、WT1

「protein p53」

　　[★]

p53タンパク質

関: p53 protein

「p」

　　[★]

ピコ

10の-12乗

関: pico

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[WikiPathways-195] The interactive pathway map can be edited at WikiPathways: "FluoropyrimidineActivity_WP1601".

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p53