Thursday, August 30, 2012

Stat Signaling and Cancer


Contributed by Kimberly Holloway, Ph.D.

Ten years following the discovery of the first Stat (signal transducer and activators of transcription), Stat1 (1), the identification of closely related proteins and isoforms, Stat 1α/β, 2, 3α/β/γ, 4α/β, 5a/b, 6, formed the Stat family (2). The Stat signaling pathway involves the ligand-dependent activation of cell-surface cytokine receptors via dimerization.  Cytokine binding and receptor dimerization subsequently activate receptor-associated tyrosine kinases (i.e. Jak 1-3 and TyK2) via autophosphorylation.  The activated tyrosine kinases phosphorylate the receptors which then recruit and aid in the phosphorylation of corresponding Stats.  The Stats dimerize, translocate to the nucleus, and function as transcription factors (3).
Stats are critical integrators of cytokine and growth factor receptor signaling required for cell growth, survival, differentiation, and motility (3).  Therefore, Stats are involved in physiological as well as pathophysiological processes.  For example, within normal mammary development, Stat5a is essential for lobuloalveolar development and expression of milk protein genes, Stat3 is an essential mediator of involution, and Stat6 regulates commitment to alveolar lineage (2).  Stat1 and 4 are differentially expressed during the mammary developmental cycle (2).  It has also been shown that constitutive activation of Stat3 and 5 is frequently associated with mammary tumors (4).  This correlation is not exclusive to mammary tumors; whereas, Stat3, 5, and/or 1 have been studied to be constitutively activated in head and neck cancer, lung cancer, melanoma, myeloma, lymphoma, or leukemia (5).

The dual function of Stats in normal development and cancer-associated uncontrolled proliferation or failure of apoptosis positions this family of transcription factors as potential therapeutic targets; and the future of generating efficient Stat-dependent therapeutic strategies will be dependent on specifically characterizing the regulators and mediators of Stat activation aberrantly modified in the pathophysiological environment.

Related Bethyl Antibodies 

 
Gene ID
Target
207
208
598
868
1387
867
9646
84444
5595
5594
9146
9146
3667
8660
3717
4771
9111
4851
2033
5595
5296
5292
5311
5770
5781
6654
6655
10253
8027
6772
6773
6774
6776
6777
6778


References
1.   Schindler C, Shuai K, Prezioso VR, Darnell Jr JE. Interferon-dependent tyrosine phosphorylation of a latent cytoplasmic transcription factor. Science 1992, 257(5071):809-813.
2.   Watson CJ, Neoh K. The Stat family of transcription factors have diverse roles in mammary gland development. Seminars in Cell & Developmental Biology 2008, 19:401-406
3.   Clevenger CV. Roles and Regulation of Stat Family Transcription Factors in Human Breast Cancer. American Journal of Pathology 2004, 165(5):1449-1460.
4.   Watson CJ. Stat Transcription Factors in Mammary Gland Development and Tumorigenesis. Journal of Mammary Gland Biology and Neoplasia  2001, 6(1): 115-127.
5.   Bowman T, Garcia R, Turkson J, Jove R. Stats in oncogenesis. Oncogene 2000, 19:2474-2488.