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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2016/02/19 23:46:41」(JST)

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Signal Transducer and Activator of Transcription 5 refers to two highly related proteins, STAT5A and STAT5B, which are part of the seven-membered STAT family of proteins. Though STAT5A and STAT5B are encoded by separate genes, the proteins are 90% identical at the amino acid level.^[1] STAT5 proteins are involved in cytosolic signalling and in mediating the expression of specific genes.^[2] Aberrant STAT5 activity has been shown to be closely connected to a wide range of human cancers,^[3] and silencing this aberrant activity is an area of active research in medicinal chemistry.^[4]

Activation and function

In order to be functional, STAT5 proteins must first be activated. This activation is carried out by kinases associated with transmembrane receptors:^[3]

first, ligands binding to these transmembrane receptors on the outside of the cell activate the kinases;
second, the stimulated kinases add a phosphate group to a specific tyrosine residue on the receptor;
STAT5 then binds to these phosphorylated-tyrosines using their SH2 domain (STAT domains illustrated below);
the bound STAT5 is then phosphorylated by the kinase, the phosphorylation occurring at particular tyrosine residues on the C-terminus of the protein;
phosphorylation causes STAT5 to dissociate from the receptor;
the phosphorylated STAT5 finally goes on to form either homodimers, STAT5-STAT5, or heterodimers, STAT5-STATX, with other STAT proteins. The SH2 domains of the STAT5 proteins are once again used for this dimerization. STAT5 can also form homo-tetramers, usually in concert with the histone methyltransferase EZH2, and act as a transcriptional repressor.^[5]

STAT5 Activation

In the activation pathway illustrated to the left, the ligand involved is a cytokine and the specific kinase taking part in activation is JAK. The dimerized STAT5 represents the active form of the protein, which is ready for translocation into the nucleus.

Once in the nucleus, the dimers bind to STAT5 response elements, inducing transcription of specific sets of genes. Upregulation of gene expression by STAT5 dimers has been observed for genes dealing with:^[2]

controlled cell growth and division, or cell proliferation
programmed cell death, or apoptosis
cell specialization, or differentiation and
inflammation.

Activated STAT5 dimers are, however, short-lived and the dimers are made to undergo rapid deactivation. Deactivation may be carried out by a direct pathway, removing the phosphate groups using phosphatases like PIAS or SHP-2 for example, or by an indirect pathway, which involves reducing cytokine signalling.^[6]

STAT5 and cancer

STAT5 has been found to be constitutively phosphorylated in cancer cells,^[4] implying that the protein is always present in its active form. This constant activation is brought about either by mutations or by aberrant expressions of cell signalling, resulting in poor regulation, or complete lack of control, of the activation of transcription for genes influenced by STAT5. This leads to constant and increased expression of these genes. For example, mutations may lead to increased expression of anti-apoptotic genes, the products of which actively prevent cell death. The constant presence of these products preserve the cell in spite of it having become cancerous, causing the cell to eventually become malignant.

Treatment approaches

Attempts at treatment for cancer cells with constitutively phosphorylated STAT5 have included both indirect and direct inhibition of STAT5 activity. While more medicinal work has been done in indirect inhibition, this approach can lead to increased toxicity in cells and can also result in non-specific effects, both of which are better handled by direct inhibition.^[4]

Indirect inhibition targets kinases associated with STAT5, or targets proteases that carry out terminal truncation of proteins. Different inhibitors have been designed to target different kinases:

inhibition of BCR/ABl constitutes the basis of the functioning of drugs like imatinib^[7]
inhibition of FLT3 is carried out by drugs like lestaurtinib^[8]
inhibition of JAK2 is carried out by the drug CYT387, which was successful in preclinical trials and is currently undergoing clinical trials.^[9]

Domains of STAT proteins

Direct inhibition of STAT5 activity makes use of small molecule inhibitors that prevent STAT5 from properly binding to DNA, or prevent proper dimerization. The inhibiting of DNA binding utilizes RNA interference,^[10] antisense oligodeoxynucleotide,^[10] and short hairpin RNA.^[11] The inhibition of proper dimerization, on the other hand, is brought about by the use of small molecules that target the SH2 domain. Recent work on drug development in the latter field have proved particularly effective.^[12]

References

^ Grimley PM, Dong F, Rui H (June 1999). "Stat5a and Stat5b: fraternal twins of signal transduction and transcriptional activation". Cytokine Growth Factor Rev. 10 (2): 131–57. doi:10.1016/S1359-6101(99)00011-8. PMID 10743504.
^ ^a ^b Nosaka T, Kawashima T, Misawa K, Ikuta K, Mui AL, Kitamura T (September 1999). "STAT5 as a molecular regulator of proliferation, differentiation and apoptosis in hematopoietic cells". EMBO J. 18 (17): 4754–65. doi:10.1093/emboj/18.17.4754. PMC 1171548. PMID 10469654.
^ ^a ^b Tan SH, Nevalainen MT (June 2008). "Signal transducer and activator of transcription 5A/B in prostate and breast cancers". Endocr. Relat. Cancer 15 (2): 367–90. doi:10.1677/ERC-08-0013. PMID 18508994.
^ ^a ^b ^c Cumaraswamy AA, Todic A, Resetca D, Minden MD, Gunning PT (January 2012). "Inhibitors of Stat5 protein signalling". MedChemComm 3 (1): 22. doi:10.1039/C1MD00175B.
^ Mandal M, Powers SE, Maienschein-Cline M, Bartom ET, Hamel KM, Kee BL, Dinner AR, Clark MR (December 2011). "Epigenetic repression of the Igk locus by STAT5-mediated recruitment of the histone methyltransferase Ezh2". Nat. Immunol. 12 (12): 1212–20. doi:10.1038/ni.2136. PMC 3233979. PMID 22037603.
^ Shuai K, Halpern J, ten Hoeve J, Rao X, Sawyers CL (July 1996). "Constitutive activation of STAT5 by the BCR-ABL oncogene in chronic myelogenous leukemia". Oncogene 13 (2): 247–54. PMID 8710363.
^ Druker BJ, Tamura S, Buchdunger E, Ohno S, Segal GM, Fanning S, Zimmermann J, Lydon NB (May 1996). "Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells". Nat. Med. 2 (5): 561–6. doi:10.1038/nm0596-561. PMID 8616716.
^ Levis M, Allebach J, Tse KF, Zheng R, Baldwin BR, Smith BD, Jones-Bolin S, Ruggeri B, Dionne C, Small D (June 2002). "A FLT3-targeted tyrosine kinase inhibitor is cytotoxic to leukemia cells in vitro and in vivo". Blood 99 (11): 3885–91. doi:10.1182/blood.V99.11.3885. PMID 12010785.
^ Pardanani A, Lasho T, Smith G, Burns CJ, Fantino E, Tefferi A (August 2009). "CYT387, a selective JAK1/JAK2 inhibitor: in vitro assessment of kinase selectivity and preclinical studies using cell lines and primary cells from polycythemia vera patients". Leukemia 23 (8): 1441–5. doi:10.1038/leu.2009.50. PMID 19295546.
^ ^a ^b Behbod F, Nagy ZS, Stepkowski SM, Karras J, Johnson CR, Jarvis WD, Kirken RA (October 2003). "Specific inhibition of Stat5a/b promotes apoptosis of IL-2-responsive primary and tumor-derived lymphoid cells" (PDF). J. Immunol. 171 (8): 3919–27. doi:10.4049/jimmunol.171.8.3919. PMID 14530308.
^ Klosek SK, Nakashiro K, Hara S, Goda H, Hamakawa H (October 2008). "Stat3 as a molecular target in RNA interference-based treatment of oral squamous cell carcinoma". Oncol. Rep. 20 (4): 873–8. doi:10.3892/or_00000085. PMID 18813829.
^ Page BD, Khoury H, Laister RC, Fletcher S, Vellozo M, Manzoli A, Yue P, Turkson J, Minden MD, Gunning PT (February 2012). "Small molecule STAT5-SH2 domain inhibitors exhibit potent antileukemia activity". J. Med. Chem. 55 (3): 1047–55. doi:10.1021/jm200720n. PMID 22148584.

UpToDate Contents

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1. 慢性骨髄性白血病の細胞生物学および分子生物学 cellular and molecular biology of chronic myeloid leukemia
2. X連鎖重度複合型免疫不全（SCID） x linked severe combined immunodeficiency scid
3. JAK3欠損を伴う重度複合型免疫不全（SCID） severe combined immunodeficiency scid with jak3 deficiency
4. 先天性赤血球増多症および真性多血症の分子学的病因 molecular pathogenesis of congenital polycythemic disorders and polycythemia vera
5. ヘルパーT細胞サブセット：疾患における分化および役割 t helper subsets differentiation and role in disease

English Journal

T helper 9 cells induced by plasmacytoid dendritic cells regulate interleukin-17 in multiple sclerosis.

Ruocco G1, Rossi S2, Motta C2, Macchiarulo G2, Barbieri F2, De Bardi M1, Borsellino G1, Finardi A3, Grasso MG4, Ruggieri S5, Gasperini C5, Furlan R3, Centonze D2, Battistini L1, Volpe E1.
Clinical science (London, England : 1979).Clin Sci (Lond).2015 Aug 1;129(4):291-303. doi: 10.1042/CS20140608.
Multiple sclerosis (MS) is a chronic disease of the central nervous system (CNS) characterized by persistent inflammation orchestrated by cluster of differentiation (CD) 4 T helper (Th) cells. In particular, Th1 and Th17 cells amplify, whereas T regulatory (Treg) cells moderate inflammation. The rol
PMID 25700150

Antitumor immunostimulatory activity of polysaccharides from Salvia chinensis Benth.

Shu G1, Zhao W1, Yue L2, Su H3, Xiang M4.
Journal of ethnopharmacology.J Ethnopharmacol.2015 Jun 20;168:237-47. doi: 10.1016/j.jep.2015.03.065. Epub 2015 Apr 6.
ETHNOPHARMACOLOGICAL RELEVANCE: Salvia chinensis Benth (S. chinensis) is a traditional herb applied in the treatment of hepatocellular carcinoma (HCC). Polysaccharides abundantly exist in this plant. However, it remains poorly understood if polysaccharides from S. chinensis (PSSC) contribute to its
PMID 25858511

Nucleophosmin overexpression is associated with poor survival in astrocytoma.

Kuo YH1,2, Chen YT1,3, Tsai HP1, Chai CY1,2,3,4, Kwan AL5,6,7.
APMIS : acta pathologica, microbiologica, et immunologica Scandinavica.APMIS.2015 Jun;123(6):515-22. doi: 10.1111/apm.12381. Epub 2015 Apr 23.
The multiple functions of the protein nucleophosmin (NPM) include the regulation and balance of cell growth, proliferation, and apoptosis. Many cancers have suspected associations with overexpression of NPM or with mutation of the NPM gene. Although NPM and anaplastic lymphoma kinase fusion proteins
PMID 25907517

Japanese Journal

Activation of STAT5 confers imatinib resistance on leukemic cells through the transcription of TERT and MDR1

YAMADA 　Osamu,OZAKI 　Kohji,FURUKAWA 　Thoru,MACHIDA 　Mitsuyo,Yan-Hua Wang,MOTOJI 　Toshiko,MITSUISHI 　Tsuyoshi,AKIYAMA 　Masaharu,YAMADA 　Hisashi,KAWAUCHI 　Kiyotaka,Rumiko Matsuoka
Cellular Signalling 23(7), 1119-1127, 2011-07
NAID 120003145454

Involvement of STAP-2 in Brk-mediated phosphorylation and activation of STAT5 in breast cancer cells

IKEDA Osamu,MIZUSHIMA Akihiro,SEKINE Yuichi,YAMAMOTO Chikako,MUROMOTO Ryuta,NANBO Asuka,ORITANI Kenji,YOSHIMURA Akihiko,MATSUDA Tadashi
Cancer science 102(4), 756-761, 2011-04-10
NAID 10029292209

52.転写因子STAT5をバイオマーカーとした化学物質曝露の評価(第28回産業医科大学学会総会学術講演・展示抄録集)

吉田安宏,一瀬豊日,丁寧,欅田尚樹
産業医科大学雑誌 33(1), 118, 2011-03-01
NAID 110008574540

Related Pictures

★リンクテーブル★

リンク元	「プロラクチン」
拡張検索	「STAT5転写因子」
関連記事	「STA」「STAT」

「プロラクチン」

signal transducer and activator of transcription 5B
	STAT5B
Identifiers
Symbol	STAT5B
Entrez	6777
HUGO	11367
OMIM	604260
RefSeq	NM_012448
UniProt	P51692
Other data
Locus	Chr. 17 q11.2

signal transducer and activator of transcription 5A
	STAT5A
Identifiers
Symbol	STAT5A
Alt. symbols	STAT5
Entrez	6776
HUGO	11366
OMIM	601511
RefSeq	NM_003152
UniProt	P42229
Other data
Locus	Chr. 17 q11.2

　　[★]

英: prolactin (Z), PRL, lactotrophic hormone (Z)
関: ホルモン、下垂体前葉ホルモン

分類

下垂体ホルモン

性状

ペプチド
199 aa., 198aa 21.5kDa(HIM.2204)
成長ホルモン、hPL(human placental lactogen)に構造が似る　→　common GH-PRL-hPL precursor gene on chromosome 6

産生組織

下垂体前葉：lactrope(20%を占める)で産生される。lactropeはsomatotropeと同じ前駆細胞に由来するので、GHとPRLを産生する線種もある。lactropeのpopulationはエストロゲンの影響下にあって、また妊娠のlast two trimestersおよび授乳期の最初の2,3ヶ月に過形成が起こる。(HIM.2204)
わずかに下記組織で産生される (SP.888)

胎盤脱落膜細胞、リンパ球、視床下部神経細胞

標的組織

乳腺

生理作用

プロラクチンの生理作用はエストロゲンにより阻害される(SP.888)　←　分娩後に初めて乳汁産生が起こる

乳汁産生促進

乳腺上皮細胞の増殖↑
乳汁産生↑(カゼイン・ラクトアルブミン・ラクトグロブリン・乳糖・脂肪酸の産生↑)

HIM.2204

プロラクチンは乳汁分泌を維持し、生殖機能を低下させ、性的衝動を減退させる。
これらの機能は、母体の乳汁分泌を持続し妊娠によって中断しないことを確実にすることにかなう。
プロラクチンは視床下部のGnRHや下垂体でのGnHの分泌を抑制し、男女ともに視床下部のステロイド合成を減少させる。
卵巣では、卵胞形成を阻止し、顆粒層細胞のアロマターゼ活性を抑制し、低エストロゲン症と無排卵をきたす。
プロラクチンは黄体退縮作用を持ち、月経周期の黄体周を短縮させ、あるいは不十分にする。
これらのホルモンの変化により性欲が減退し、生殖力が低下する。

作用機序

プロラクチン受容体→JAK2-STAT5→遺伝子発現

分泌調節

プロラクチンの分泌制御はユニークであり、ドパミンによるD2受容体を介した抑制を受ける。
プロラクチンは視床下部に対して抑制的に作用し、間接的に下垂体前葉からのプロラクチン放出が抑制される　(短環フィードバック)
視床下部からドーパミンが放出され、下垂体前葉に対し抑制的に作用する。

SP.889改変

分泌促進	分泌抑制
吸乳エストロゲン妊娠睡眠ストレスプロラクチン放出因子セロトニン作動薬ドーパミン受容体遮断薬 TRH	ドーパミン受容体作動薬プロラクチン

HIM.2204

パルス状に分泌
REM睡眠時に分泌↑　　←　成長ホルモンと似ている？
血中濃度のピークは朝方(4-6時)で、30ng/ml
半減期は50分

妊娠・出産との関連

授乳する場合、出産後3-4ヶ月かかって緩やかに下降。　→　同時期の月経再開と関連

基準値

検査の本？

小児(10歳まで)　1.2-12ng/ml
成人女性　1.5-15ng/ml
成人男性　1.5-10ng/ml
高齢者(70歳以上)　1.2-15ng/ml
以上、WHO　1st IRP-PRL(75/504)を標準品とした値。なお、妊婦、産褥期には高値となりこの基準値はあてはまらない

HIM.2204

10-25 ng/ml (女性)
10-20 ng/ml (男性)

検査

プロラクチン分泌促進テスト：TRHテスト
プロラクチン分泌抑制テスト：ブロモクリプチン負荷テスト

臨床関連

高プロラクチン血症

「STAT5転写因子」

　　[★]

英: STAT5 transcription factor

「STA」

　　[★]

「STAT」

　　[★] signal transducer and activator of transcription

[pmid10743504-1] Grimley PM, Dong F, Rui H (June 1999). "Stat5a and Stat5b: fraternal twins of signal transduction and transcriptional activation". Cytokine Growth Factor Rev. 10 (2): 131–57. doi:10.1016/S1359-6101(99)00011-8. PMID 10743504.

[Nosaka_1999-2] Nosaka T, Kawashima T, Misawa K, Ikuta K, Mui AL, Kitamura T (September 1999). "STAT5 as a molecular regulator of proliferation, differentiation and apoptosis in hematopoietic cells". EMBO J. 18 (17): 4754–65. doi:10.1093/emboj/18.17.4754. PMC 1171548. PMID 10469654.

[Tan_2008-3] Tan SH, Nevalainen MT (June 2008). "Signal transducer and activator of transcription 5A/B in prostate and breast cancers". Endocr. Relat. Cancer 15 (2): 367–90. doi:10.1677/ERC-08-0013. PMID 18508994.

[Cumaraswamy_2012-4] Cumaraswamy AA, Todic A, Resetca D, Minden MD, Gunning PT (January 2012). "Inhibitors of Stat5 protein signalling". MedChemComm 3 (1): 22. doi:10.1039/C1MD00175B.

[pmid22037603-5] Mandal M, Powers SE, Maienschein-Cline M, Bartom ET, Hamel KM, Kee BL, Dinner AR, Clark MR (December 2011). "Epigenetic repression of the Igk locus by STAT5-mediated recruitment of the histone methyltransferase Ezh2". Nat. Immunol. 12 (12): 1212–20. doi:10.1038/ni.2136. PMC 3233979. PMID 22037603.

[Shuai_1996-6] Shuai K, Halpern J, ten Hoeve J, Rao X, Sawyers CL (July 1996). "Constitutive activation of STAT5 by the BCR-ABL oncogene in chronic myelogenous leukemia". Oncogene 13 (2): 247–54. PMID 8710363.

[Druker_1996-7] Druker BJ, Tamura S, Buchdunger E, Ohno S, Segal GM, Fanning S, Zimmermann J, Lydon NB (May 1996). "Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells". Nat. Med. 2 (5): 561–6. doi:10.1038/nm0596-561. PMID 8616716.

[Levis_2002-8] Levis M, Allebach J, Tse KF, Zheng R, Baldwin BR, Smith BD, Jones-Bolin S, Ruggeri B, Dionne C, Small D (June 2002). "A FLT3-targeted tyrosine kinase inhibitor is cytotoxic to leukemia cells in vitro and in vivo". Blood 99 (11): 3885–91. doi:10.1182/blood.V99.11.3885. PMID 12010785.

[Pardanani_2009-9] Pardanani A, Lasho T, Smith G, Burns CJ, Fantino E, Tefferi A (August 2009). "CYT387, a selective JAK1/JAK2 inhibitor: in vitro assessment of kinase selectivity and preclinical studies using cell lines and primary cells from polycythemia vera patients". Leukemia 23 (8): 1441–5. doi:10.1038/leu.2009.50. PMID 19295546.

[Behbod_2003-10] Behbod F, Nagy ZS, Stepkowski SM, Karras J, Johnson CR, Jarvis WD, Kirken RA (October 2003). "Specific inhibition of Stat5a/b promotes apoptosis of IL-2-responsive primary and tumor-derived lymphoid cells" (PDF). J. Immunol. 171 (8): 3919–27. doi:10.4049/jimmunol.171.8.3919. PMID 14530308.

[pmid18813829-11] Klosek SK, Nakashiro K, Hara S, Goda H, Hamakawa H (October 2008). "Stat3 as a molecular target in RNA interference-based treatment of oral squamous cell carcinoma". Oncol. Rep. 20 (4): 873–8. doi:10.3892/or_00000085. PMID 18813829.

[Page_2012-12] Page BD, Khoury H, Laister RC, Fletcher S, Vellozo M, Manzoli A, Yue P, Turkson J, Minden MD, Gunning PT (February 2012). "Small molecule STAT5-SH2 domain inhibitors exhibit potent antileukemia activity". J. Med. Chem. 55 (3): 1047–55. doi:10.1021/jm200720n. PMID 22148584.

匿名

検索

案内

案内

STAT5

Wikipedia preview

wiki en

Contents

Activation and function

STAT5 and cancer

Treatment approaches

References

UpToDate Contents

English Journal

Japanese Journal

Related Links

Related Pictures

★リンクテーブル★

「プロラクチン」

分類

性状

産生組織

標的組織

生理作用

HIM.2204

作用機序

分泌調節

SP.889改変

HIM.2204

妊娠・出産との関連

基準値

検査の本？

HIM.2204

検査

臨床関連

「STAT5転写因子」

「STA」

「STAT」