Nuclear Receptor Signaling

There are three members of the steroid receptor co-activator (SRC) family of proteins: SRC-1 (NCoA-1), SRC-2 (TIF2/GRIP1/NCoA-2) and SRC-3 (ACTR/pCIP/RAC3/TRAM-1/AIB1). The SRC family members all share significant structural homology and function in a similar fashion to stimulate transcription mediated by nuclear hormone receptors and other transcriptional activators such as STAT3, NF-κB, E2F1 and p53 (1-4). Two SRC proteins, SRC-1 and SRC-3, function as histone acetyltransferases (5,6). In addition, all three family members can recruit other histone acetyltransferases (CBP/p300, PCAF) and histone methyltransferases (PRMT1, CARM1) to target promoters and cooperate to enhance expression of many genes (5-8). The SRC proteins play important roles in multiple physiological processes including cell proliferation, cell survival, somatic cell growth, mammary gland development, female reproductive function and vasoprotection (9). SRC-1 and SRC-3 are conduits for kinase-mediated growth factor signaling to the estrogen receptor and other transcriptional activators. Seven SRC-1 phosphorylation sites and six SRC-3 phosphorylation sites have been identified, which are induced by steroids, cytokines and growth factors and involve multiple kinase signaling pathways (9-11). All three SRC family members are associated with increased activity of nuclear receptors in breast, prostate and ovarian carcinomas. In addition, SRC-3 is frequently amplified or over-expressed in a number of cancers (12), and SRC-1/PAX3 and SRC-2/MYST3 translocations are found associated with rhabdomyosarcoma and acute myeloid leukemia, respectively (13,14).

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2. Na, S.Y. et al. (1998) J. Biol. Chem. 273, 10831-10834.
3. Louie, M.C. et al. (2004) Mol. Cell Biol. 24, 5157-5171.
4. Lee, S.K. et al. (1999) Mol. Endocrinol. 13, 1924-1933.
5. Spencer, T.E. et al. (1997) Nature 389, 194-198.
6. Chen, H. et al. (1997) Cell 90, 569-580.
7. Koh, S.S. et al. (2001) J. Biol. Chem. 276, 1089-1098.
8. Chen, D. et al. (1999) Science 284, 2174-2177.
9. Wu, R.C. et al. (2004) Mol. Cell 15, 937-949.
10. Rowan, B.G. et al. (2000) J. Biol. Chem. 275, 4475-4483.
11. Zhou, H.J. et al. (2005) Cancer Res. 65, 7976-7983.
12. Torres-Arzayus, M.I. et al. (2004) Cancer Cell 6, 263-274.
13. Wachtel, M. et al. (2004) Cancer Res. 64, 5539-5545.
14. Deguchi, K. et al. (2003) Cancer Cell 3, 259-271.

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SRC-1 Blocking Peptide

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