The thesis primarily addresses the role of transcriptional corepressor and signal transduction cascades in regulatingandrogen receptor (AR) activity. AR is a ligand-activated transcription factor and is important for the development ofmale phenotype. Malfunctioning of AR function has been implicated in the progression of the prostate cancer (CaP).Clinical management of the CaP most often involves the administration of anti-hormones (Cas, CPA) that bind to ARand turn it transcriptionally incompetent and consequently regression of the tumor. Eventually though emergesresistance to therapy 3-4 semesters post-treatment but unfortunately modern medicine doesn t offer any cure at thispoint. To safeguard the AR function, corepressor molecules negatively modulate AR function on its target geneshence suggested to have protective role against the CaP. Gene regulation by AR and corepressors can be influenced byactivated signal transduction machinery often abruptly activated in CaP cells.
The work pursued here in part shows how partial agonist CPA modulates the expression of target genes PSCA andMaspin. It also highlights how interaction of corepressor SMRT is modulated by signal transduction pathways in vivo.The work demonstrates the role of Src kinase pathway in regulating AR function in androgen-independent CaP cells.Inhibiting Src by chemical inhibitor PP2, leads to decrease in AR recruitment on target genes in vivo. Also it decreasestransactivation potential of AR on various target genes. The work also shows that inhibition of Src leads to loss oftarget gene induction in response to agonist and growth retardation of C4-2, hormone-independently growing cells.This work also demonstrates the discovery of a new AR corepressor LCoR. Corepressor LCoR potently represses ARtransactivation not only in anti-hormone but also in a hormone-dependent manner in CV1 cells. Versatility inrepression by LCoR evidenced from the experiments showing potent in vivo repression of AR T877A hot spot mutantand another AR mutant which does not interact and thereby not repressed by many other corepressors. This work alsoshows that for its interaction with AR LCoR uses its C-terminus, which harbours HLH domain that interacts with theDBD of AR in vivo. Intriguingly LCoR shows only marginal repression of endogenous AR in CaP cells. This workshows that LCoR is functionally weakened by Src kinase pathway in CaP cells in repressing AR function. Inhibitionof Src by Src inhibitor PP2 enhances autonomous silencing function of LCoR. In addition, this inhibition by PP2enhances its ability to interact and thereby repress AR in CaP. Overexpression of stably-integrated corepressor LCoRin CaP cells leads to compromised growth.
This work demonstrates the importance of molecular cross talk between corepressors and signal transduction pathwaysthat functionally modulate the corepressor function and thereby regulate AR transactivation and growth of CaP. It alsoopens an important avenue in translational cancer research implicating the role of cross talk between signalingcascades and corepressors in CaP.
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