STAT3


STAT3

The protein encoded by this gene is a member of the STAT protein family. In response to cytokines and growth factors, STAT family members are phosphorylated by the receptor associated kinases, and then form homo- or heterodimers that translocate to the cell nucleus where they act as transcription activators. This protein is activated through phosphorylation in response to various cytokines and growth factors including IFNs, EGF, IL5, IL6, HGF, LIF and BMP2. STAT3 mediates the expression of a variety of genes in response to cell stimuli, and thus plays a key role in many cellular processes such as cell growth and apoptosis. The small GTPase Rac1 has been shown to bind and regulate the activity of this protein. PIAS3 protein is a specific inhibitor of this protein. Three alternatively spliced transcript variants encoding distinct isoforms have been described.

The binding of IL-6 family cytokines (including IL-6, oncostatin M and leukemia inhibitory factor) to the gp130 receptor triggers STAT3 phosphorylation by JAK2. EGF-R and certain other receptor tyrosine kinases, such as c-MET phosphorylate STAT3 in response to their ligands. [cite online journal|author=Yuan ZL, Guan YJ, Wang L, Wei W, Kane AB and Chin YE | year=2004 | title=Central role of the threonine residue within the p+1 loop of receptor tyrosine kinase in STAT3 constitutive phosphorylation in metastatic cancer cells | journal=Mol Cell Biol | volume=24 | issue=21 | pages=9390-9400 | id=15485908] STAT3 is also a target of the c-src non-receptor tyrosine kinase. [cite online journal| author=Silva CM | year=2004 | title=Role of STATs as downstream signal transducers in Src family kinase-mediated tumorigenesis | journal=Oncogene | volume=23 | issue=48 | pages=8017-8023 | id=15489919]

STAT3-deficient mouse embryos can not develop beyond embryonic day 7 (E7.0), when gastrulation initiates. [cite online journal| author=Takeda K, Noguchi K, Shi W, Tanaka T, Matsumoto M, Yoshida N, Kishimoto T and Akira S | year=1997 | title=Targeted disruption of the mouse Stat3 gene leads to early embryonic lethality | journal=PNAS | volume=94 | issue=8 | pages=3801-3084 | id=9108058] It appears that at these early stages of development, STAT3 activation is required for self-renewal of embryonic stem cells (ESCs). Indeed, LIF, which is supplied to ESC cultures to maintain their undifferentiated state, can be omitted if STAT3 is activated through some other means. [cite online journal| author=Matsuda T, Nakamura T, Nakao K, Arai T, Katsuki M, Heike T and Yokota T | year=1999 | title=STAT3 activation is sufficient to maintain an undifferentiated state of mouse embryonic stem cells | journal=EMBO J | volume=18 | issue=15 | pages=4261-4269 | id=10428964]

Constitutive STAT3 activation is associated with various human cancers and commonly suggests poor prognosis.cite online journal| author=Klampfer L | year=2006 | title=Signal transducers and activators of transcription (STATs): Novel targets of chemopreventive and chemotherapeutic drugs | journal=Curr Cancer Drug Targets | volume=6 | issue=2 | pages=107-121 | id=16529541] [cite online journal| author=Alvarez JV, Greulich H, Sellers WR, Meyerson M and Frank DA | year=2006 | title=Signal transducer and activator of transcription 3 is required for the oncogenic effects of non-small-cell lung cancer-associated mutations of the epidermal growth factor receptor | journal=Cancer Res | volume=66 | issue=6 | pages=3162-3168 | id=16540667] [cite online journal| author=Yin W, Cheepala S, Roberts JN, Syson-Chan K, Digiovanni J and Clifford JL | year=2006 | title=Active Stat3 is required for survival of human squamous cell carcinoma cells in serum-free conditions | journal=Mol Cancer | volume=5 | issue=1 | article=15 | id=16603078] [cite online journal| author=Kusaba T, Nakayama T, Yamazumi K, Yakata Y, Yoshizaki A, Inoue K, Nagayasu T and Sekine I | year=2006 | title=Activation of STAT3 is a marker of poor prognosis in human colorectal cancer | journal=Oncol Rep | volume=15 | issue=6 | pages=1445-1451 | id=16685378] It has anti-apoptotic as well as proliferative effects.

References

Further reading

PBB_Further_reading
citations =
*cite journal | author=Hoey T, Grusby MJ |title=STATs as mediators of cytokine-induced responses. |journal=Adv. Immunol. |volume=71 |issue= |pages= 145–62 |year= 1999 |pmid= 9917912 |doi=
*cite journal | author=Kisseleva T, Bhattacharya S, Braunstein J, Schindler CW |title=Signaling through the JAK/STAT pathway, recent advances and future challenges. |journal=Gene |volume=285 |issue= 1-2 |pages= 1–24 |year= 2002 |pmid= 12039028 |doi=
*cite journal | author=Joseph AM, Kumar M, Mitra D |title=Nef: "necessary and enforcing factor" in HIV infection. |journal=Curr. HIV Res. |volume=3 |issue= 1 |pages= 87–94 |year= 2005 |pmid= 15638726 |doi=
*cite journal | author=Inghirami G, Chiarle R, Simmons WJ, "et al." |title=New and old functions of STAT3: a pivotal target for individualized treatment of cancer. |journal=Cell Cycle |volume=4 |issue= 9 |pages= 1131–3 |year= 2006 |pmid= 16082218 |doi=
*cite journal | author=Leeman RJ, Lui VW, Grandis JR |title=STAT3 as a therapeutic target in head and neck cancer. |journal=Expert opinion on biological therapy |volume=6 |issue= 3 |pages= 231–41 |year= 2006 |pmid= 16503733 |doi= 10.1517/14712598.6.3.231
*cite journal | author=Aggarwal BB, Sethi G, Ahn KS, "et al." |title=Targeting signal-transducer-and-activator-of-transcription-3 for prevention and therapy of cancer: modern target but ancient solution. |journal=Ann. N. Y. Acad. Sci. |volume=1091 |issue= |pages= 151–69 |year= 2007 |pmid= 17341611 |doi= 10.1196/annals.1378.063

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