The effects of cAMP on cell growth and proliferation have been intensely investigated, but its mechanisms of action are not completely understood. The effects of cAMP are predominantly mediated by the cAMP-dependent protein kinase (PKA), which is composed of two distinct subunits, catalytic (C) and regulatory (R), forming a tetrameric holoenzymes, R2C2. The type I regulatory alpha (RIalpha) subunit expression is associated with hyperproliferation in human breast tissue and its overexpression in human breast cancer correlates with malignancy and poor prognosis. Increased expression of RI? stimulates growth, whereas overexpression of the C subunit does not produce such consequence. Most recently, RIalpha was shown to be a tumor suppressor gene in Carney Complex Syndrome. We have demonstrated previously novel interaction of RIalpha that is independent of the C subunit kinase activity. In this application, we show by yeast two-hybrid interaction cloning experiment that RIalpha associates with a novel BTB/POZ domain zinc finger transcription factor, termed RIalpha-associated zinc finger protein (RIAZ). We demonstrate that RIAZ is a cAMP-responsive transcriptional activator regulated by its interaction with RIalpha and potential cooperation with the cAMP-response element binding protein (CREB). We show further that RIAZ is aberrantly expressed in approximately 15% of human primary breast cancer. Furthermore, overexpression of RIAZ causes growth inhibition measured by [3H]thymidine uptake. The growth inhibition is enhanced by cAMP but not affected by the PKA inhibitor H-89. We hypothesize that RI? interaction with RIAZ may be a novel transcriptional mechanism in growth inhibition transduced by cAMP. In this proposal, we will: (1) determine the mechanisms of RI? interaction with RIAZ and regulation by cAMP; (2) investigate the mechanisms of RIAZ transcriptional response to cAMP; and (3) investigate the mechanisms of growth control by RI? interaction with RIAZ in response to cAMP. Our results will shed light on this novel interaction of RIalpha with RIAZ in growth inhibition.
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