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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2016/06/30 10:11:43」(JST)

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Myc (c-Myc) is a regulator gene that codes for a transcription factor. The protein encoded by this gene is a multifunctional, nuclear phosphoprotein that plays a role in cell cycle progression, apoptosis and cellular transformation.^[1]

A mutated version of Myc is found in many cancers, which causes Myc to be constitutively (persistently) expressed. This leads to the unregulated expression of many genes, some of which are involved in cell proliferation, and results in the formation of cancer.^[1] A common human translocation involving Myc is critical to the development of most cases of Burkitt lymphoma.^[2] Malfunctions in Myc have also been found in carcinoma of the cervix, colon, breast, lung and stomach.^[1] Myc is thus viewed as a promising target for anti-cancer drugs.^[3]

In the human genome, Myc is located on chromosome 8 and is believed to regulate expression of 15% of all genes^[4] through binding on enhancer box sequences (E-boxes) and recruiting histone acetyltransferases (HATs). This means that in addition to its role as a classical transcription factor, Myc also functions to regulate global chromatin structure by regulating histone acetylation both in gene-rich regions and at sites far from any known gene.^[5]

Discovery

Myc gene was first discovered in Burkitt lymphoma patients. In Burkitt lymphoma, cancer cells show chromosomal translocations, in which chromosome 8 is frequently involved. Cloning the break-point of the fusion chromosomes revealed a gene that was similar to myelocytomatosis viral oncogene (v-Myc). Thus, the newfound cellular gene was named c-Myc.

Structure

Myc protein belongs to Myc family of transcription factors, which also includes N-Myc and L-Myc genes. Myc family of transcription factors contain bHLH/LZ (basic helix-loop-helix leucine zipper) domain. Myc protein, through its bHLH structural motif can bind to DNA, while the leucine zipper domain allows the dimerization with its partner Max, another bHLH transcription factor.

Myc mRNA contains an IRES (internal ribosome entry site) that allows the RNA to be translated into protein when 5' cap-dependent translation is inhibited, such as during viral infection.

Function

Myc protein is a transcription factor that activates expression of many genes through binding enhancer box sequences (E-boxes) and recruiting histone acetyltransferases (HATs). It can also act as a transcriptional repressor. By binding Miz-1 transcription factor and displacing the p300 co-activator, it inhibits expression of Miz-1 target genes. In addition, myc has a direct role in the control of DNA replication.^[6]

Myc is activated upon various mitogenic signals such as Wnt, Shh and EGF (via the MAPK/ERK pathway). By modifying the expression of its target genes, Myc activation results in numerous biological effects. The first to be discovered was its capability to drive cell proliferation (upregulates cyclins, downregulates p21), but it also plays a very important role in regulating cell growth (upregulates ribosomal RNA and proteins), apoptosis (downregulates Bcl-2), differentiation, and stem cell self-renewal. Myc is a very strong proto-oncogene and it is very often found to be upregulated in many types of cancers. Myc overexpression stimulates gene amplification,^[7] presumably through DNA over-replication.

There have been several studies that have clearly indicated Myc's role in cell competition.^[8]

A major effect of Myc is B cell proliferation.^[9]

c-Myc induces MTDH(AEG-1) gene expression and in turn itself requires AEG-1 oncogene for its expression.

Myc-nick

Myc-nick is a cytoplasmic form of Myc produced by a partial proteolytic cleavage of full-length c-Myc and N-Myc.^[10] Myc cleavage is mediated by the calpain family of calcium-dependent cytosolic proteases.

The cleavage of Myc by calpains is a constitutive process but is enhanced under conditions that require rapid downregulation of Myc levels, such as during terminal differentiation. Upon cleavage, the C-terminus of Myc (containing the DNA binding domain) is degraded, while Myc-nick, the N-terminal segment 298-residue segment remains in the cytoplasm. Myc-nick contains binding domains for histone acetyltransferases and for ubiquitin ligases.

The functions of Myc-nick are currently under investigation, but this new Myc family member was found to regulate cell morphology, at least in part, by interacting with acetyl transferases to promote the acetylation of α-tubulin. Ectopic expression of Myc-nick accelerates the differentiation of committed myoblasts into muscle cells.

Clinical significance

Except for early response genes, Myc universally upregulates gene expression. Furthermore, the upregulation is nonlinear. Genes whose expression is already significantly upregulated in the absence of Myc are strongly boosted in the presence of Myc, whereas genes whose expression is low in the absence Myc get only a small boost when Myc is present.^[11]

Inactivation of SUMO-activating enzyme (SAE1 / SAE2) in the presence of Myc hyperactivation results in mitotic catastrophe and cell death in cancer cells. Hence inhibitors of SUMOylation may be a possible treatment for cancer.^[12]

Amplification of the MYC gene was found in a significant number of epithelial ovarian cancer cases.^[13] In TCGA datasets, the amplification of Myc occurs in several cancer types, including breast, colorectal, pancreatic, gastric, and uterine cancers.^[14]

In the experimental transformation process of normal cells into cancer cells, the MYC gene can cooperate with the RAS gene.^[15]^[16]

Expression of Myc is highly dependent on BRD4 function in some cancers.^[17]^[18] BET inhibitors have been used to successfully block Myc function in pre-clinical cancer models and are currently being evaluated in clinical trials.^[19]^[20]

Animal Models

During the discovery of Myc gene, it was realized that chromosomes that reciprocally translocate to chromosome 8 contained immunoglobulin genes at the break-point. Enhancers that normally drive expression of immunoglobin genes now lead to overexpression of Myc proto-oncogene in lymphoma cells. To study the mechanism of tumorigenesis in Burkitt lymphoma by mimicking expression pattern of Myc in these cancer cells, transgenic mouse models were developed. Myc gene placed under the control of IgM heavy chain enhancer in transgenic mice gives rise to mainly lymphomas. Later on, in order to study effects of Myc in other types of cancer, transgenic mice that overexpress Myc in different tissues (liver, breast) were also made. In all these mouse models overexpression of Myc causes tumorigenesis, illustrating the potency of Myc oncogene. In a study with mice, reduced expression of Myc was shown to induce longevity, with significantly extended median and maximum lifespans in both sexes and a reduced mortality rate across all ages, better health, cancer progression was slower, better metabolism and they had smaller bodies. also, Less TOR, AKT, S6K and other changes in energy and metabolic pathways (such as AMPK, more oxygen consumption, more body movements, etc). The study by John M. Sedivy and others used Cre-Loxp -recombinase to knockout one copy of Myc and this resulted in a "Haplo-insufficient" genotype noted as Myc+/-. The phenotypes seen oppose the effects of normal aging and are shared with many other long-lived mouse models such as CR (calorie restriction) ames dwarf, rapamycin, metformin and resveratrol. One study found that Myc and p53 genes were key to the survival of Chronic Myeloid Leukaemia (CML) cells. Targeting Myc and p53 proteins with drugs gave positive results on mice with CML.^[21]^[22]

Interactions

Myc has been shown to interact with:

ACTL6A^[23]
BRCA1^[24]^[25]^[26]^[27]
Bcl-2^[28]
Cyclin T1^[29]
CHD8^[30]
DNMT3A^[31]
EP400^[32]
GTF2I^[33]
HTATIP^[34]
let-7^[35]^[36]^[37]
MAPK1^[28]^[38]^[39]
MAPK8^[40]
MAX^[41]^[42]^[43]^[44]^[45]^[46]^[47]^[48]^[49]^[50]^[51]^[52]^[53]
MLH1^[45]
MYCBP2^[54]
MYCBP^[55]
NMI^[24]
NFYB^[56]
NFYC^[57]
P73^[58]
PCAF^[59]
PFDN5^[60]^[61]
RuvB-like 1^[23]^[32]
SAP130^[59]
SMAD2^[62]
SMAD3^[62]
SMARCA4^[23]^[41]
SMARCB1^[44]
SUPT3H^[59]
TIAM1^[63]
TADA2L^[59]
TAF9^[59]
TFAP2A^[64]
TRRAP^[23]^[42]^[43]^[59]
WDR5^[65]
YY1^[66] and
ZBTB17.^[67]^[68]

Overview of signal transduction pathways involved in apoptosis.

References

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^ Otsuki Y, Tanaka M, Kamo T, Kitanaka C, Kuchino Y, Sugimura H (February 2003). "Guanine nucleotide exchange factor, Tiam1, directly binds to c-Myc and interferes with c-Myc-mediated apoptosis in rat-1 fibroblasts". The Journal of Biological Chemistry 278 (7): 5132–40. doi:10.1074/jbc.M206733200. PMID 12446731.
^ Gaubatz S, Imhof A, Dosch R, Werner O, Mitchell P, Buettner R, Eilers M (April 1995). "Transcriptional activation by Myc is under negative control by the transcription factor AP-2". The EMBO Journal 14 (7): 1508–19. PMC 398238. PMID 7729426.
^ Thomas LR, Wang Q, Grieb BC, Phan J, Foshage AM, Sun Q, Olejniczak ET, Clark T, Dey S, Lorey S, Alicie B, Howard GC, Cawthon B, Ess KC, Eischen CM, Zhao Z, Fesik SW, Tansey WP (May 2015). "Interaction with WDR5 promotes target gene recognition and tumorigenesis by MYC". Molecular Cell 58 (3): 440–52. doi:10.1016/j.molcel.2015.02.028. PMC 4427524. PMID 25818646.
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External links

The Myc Protein
NCBI Human Myc protein
Myc cancer gene
myc Proto-Oncogene Proteins at the US National Library of Medicine Medical Subject Headings (MeSH)
Generating iPS Cells from MEFS through Forced Expression of Sox-2, Oct-4, c-Myc, and Klf4
Drosophila Myc - The Interactive Fly
FactorBook C-Myc

UpToDate Contents

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1. バーキットリンパ腫の病理学 pathobiology of burkitt lymphoma
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. びまん性大細胞型B細胞性リンパ腫の予後 prognosis of diffuse large b cell lymphoma
4. 頭頸部の扁平上皮癌化：分子学的および遺伝学的変化 head and neck squamous cell carcinogenesis molecular and genetic alterations
5. バーキットリンパ腫の疫学、臨床症状、病理学的特徴、および診断 epidemiology clinical manifestations pathologic features and diagnosis of burkitt lymphoma

English Journal

Flavopiridol: An Old Drug With New Perspectives? Implication for Development of New Drugs.

Cimini A1,2,3, d'Angelo M4, Benedetti E4, D'Angelo B5, Laurenti G6, Antonosante A4, Cristiano L4, Di Mambro A4, Barbarino M7, Castelli V4, Cinque B4, Cifone MG4, Ippoliti R4, Pentimalli F8, Giordano A9,10.
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Glioblastoma, the most common brain tumor, is characterized by high proliferation rate, invasion, angiogenesis, and chemo- and radio-resistance. One of most remarkable feature of glioblastoma is the switch toward a glycolytic energetic metabolism that leads to high glucose uptake and consumption and
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Sphingosine-1 phosphate promotes intestinal epithelial cell proliferation via S1PR2.

Chen T1, Huang Z1, Liu R2, Yang J2, Hylemon PB3, Zhou H4.
Frontiers in bioscience (Landmark edition).Front Biosci (Landmark Ed).2017 Jan 1;22:596-608.
Sphingosine-1 phosphate (S1P) is a potent bioactive lipid mediator that acts both as an intracellular signaling molecule and a natural ligand of five different G protein-coupled receptors (GPCRs), S1PR1-5. The level of S1P in intestinal tissue is abundant. Previous studies have reported that S1P pro
PMID 27814635

Detection of Nucleotide Disbalance in Cells Undergoing Oncogene-Induced Senescence.

Nikiforov MA1, Shewach DS2.
Methods in molecular biology (Clifton, N.J.).Methods Mol Biol.2017;1534:165-173.
DNA damage response has been characterized as an important mediator of senescence phenotypes induced by activated oncogenes in normal human cells. Depletion of intracellular deoxyribonucleotide pools has been recently recognized as one of the major causes for DNA damage in these cells. Cells undergo
PMID 27812878

Japanese Journal

Hippo-YAPシグナル伝達経路を介した細胞競合 (AYUMI 細胞競合の基本原理とその破綻)

医学のあゆみ 257(4), 300-304, 2016-04-23
NAID 40020804997

Mycにより制御される細胞競合の分子機構 (AYUMI 細胞競合の基本原理とその破綻)

医学のあゆみ 257(4), 285-292, 2016-04-23
NAID 40020804968

DLBCLにおけるMYC alterationの意義

血液内科 = Hematology 72(4), 487-492, 2016-04
NAID 40020854686

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★リンクテーブル★

リンク元	「悪性リンパ腫」
拡張検索	「Mycobacterium avium complex」「atypical Mycobacterium infection」「Mycoplasma meleagridis」「Mycoplasma mycoides」「Mycobacterium leprae infection」
関連記事	「M」

「悪性リンパ腫」

MYC
Available structures
PDB	Ortholog search: PDBe RCSB
List of PDB id codes
	1A93, 1EE4, 1MV0, 1NKP, 2A93, 2OR9, 4Y7R
Identifiers
Aliases	MYC, MRTL, MYCC, bHLHe39, c-Myc, v-myc avian myelocytomatosis viral oncogene homolog
External IDs	MGI: 97250 HomoloGene: 31092 GeneCards: 4609
Gene ontology
Molecular function	• DNA binding; • protein dimerization activity; • transcription factor activity, sequence-specific DNA binding; • protein complex binding; • transcriptional activator activity, RNA polymerase II core promoter proximal region sequence-specific binding; • transcription factor binding; • RNA polymerase II core promoter proximal region sequence-specific DNA binding; • E-box binding; • protein binding; • repressing transcription factor binding;
Cellular component	• cytosol; • nucleoplasm; • protein complex; • nucleolus; • nucleus;
Biological process	• Notch signaling pathway; • chromatin remodeling; • negative regulation of monocyte differentiation; • positive regulation of metanephric cap mesenchymal cell proliferation; • regulation of transcription, DNA-templated; • gene expression; • regulation of telomere maintenance; • positive regulation of epithelial cell proliferation; • positive regulation of fibroblast proliferation; • cellular response to UV; • oxygen transport; • negative regulation of apoptotic process; • negative regulation of transcription from RNA polymerase II promoter; • chromosome organization; • transcription, DNA-templated; • MAPK cascade; • cellular response to DNA damage stimulus; • positive regulation of transcription, DNA-templated; • positive regulation of cysteine-type endopeptidase activity involved in apoptotic process; • branching involved in ureteric bud morphogenesis; • cellular response to drug; • negative regulation of cell division; • fibroblast apoptotic process; • positive regulation of mesenchymal cell proliferation; • cell cycle arrest; • positive regulation of response to DNA damage stimulus; • positive regulation of cell proliferation; • positive regulation of DNA biosynthetic process; • regulation of gene expression; • canonical Wnt signaling pathway; • negative regulation of stress-activated MAPK cascade; • energy reserve metabolic process; • response to growth factor; • transcription initiation from RNA polymerase II promoter; • transforming growth factor beta receptor signaling pathway; • response to gamma radiation; • negative regulation of fibroblast proliferation; • response to drug; • positive regulation of transcription from RNA polymerase II promoter; • cellular iron ion homeostasis;
	Sources:Amigo / QuickGO
Orthologs
	4609
	17869
	ENSG00000136997
	ENSMUSG00000022346
	P01106
	P01108
	NM_002467
	NM_001177352; NM_001177353; NM_001177354; NM_010849
	NP_002458.2
	NP_001170823.1; NP_001170824.1; NP_001170825.1
	Wikidata
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