The SRC-specific functions are believed to be due to their tissue-specific expression levels, different affinities for various NRs, competition between NRs to recruit SRCs and between SRCs themselves for binding to NRs, and different post-translational modifications (PTMs) that regulate their protein levels and activity –. Even though SRC-2 is functionally and structurally related to the other two SRC members, knockout studies in mice have shown that SRC-2 plays distinct functional roles in fertility and ductal branching in mammary gland, , glucose- and lipid metabolism, , regulation of bone mass, cardiac function and progesterone-dependent cell cycle and immunity. The Steroid Receptor Coactivator (SRC) family, also known as p160 proteins, consist of the three members, SRC-1 (NCOA1), SRC-2 (NCOA2/GRIP1/TIF2), , and SRC-3 (NCOA3/AIB1/ACTR/RAC-3/pCIP/TRAM-1) –. Together, these results suggest that SRC-2 may have an antiproliferative function in breast cancer cells. In line with this, knockdown of SRC-2 also stimulated proliferation of MCF-7 cells. Interestingly, we observed decreased expression of several breast cancer tumour suppressor genes (e.g., TAGLN, EGR1, BCL11b, CAV1) in response to both SRC-2 knockdown and PKA activation, whereas the expression of a number of other genes implicated in cancer progression (e.g., RET, BCAS1, TFF3, CXCR4, ADM) was increased. In order to identify genes that may be regulated through PKA-induced downregulation of SRC-2, overlapping transcriptional targets in response to the respective treatments were characterized. Here we have characterized the global program of transcription in SRC-2-depleted MCF-7 breast cancer cells using short-hairpin RNA technology, and in MCF-7 cells exposed to PKA activating agents. Previously, we reported that activation of the cAMP-dependent protein kinase, PKA, facilitates ubiquitination and proteasomal degradation of SRC-2 which in turn leads to inhibition of SRC-2-coactivation of ERα and changed expression of the ERα target gene, pS2. However, whereas the functions of SRC-1 and SRC-3 in breast tumourigenesis have been extensively studied, little is known about the role of SRC-2. The p160/Steroid Receptor Coactivators SRC-1, SRC-2/GRIP1, and SRC-3/AIB1 are important regulators of Estrogen Receptor alpha (ERα) activity.
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