Effect of Chimaerins, Novel Receptors for Phorbol Esters, on Breast Cancer Cell Proliferation and Cell Cycle Progression
Annual summary rept. 1 Jul 2003-30 Jun 2006
PENNSYLVANIA UNIV PHILADELPHIA
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Chimaerins are a family of intracellular receptors for the phorbol ester tumor promoters and the second messenger diacylglycerol. The discovery of chimaerins challenges the traditional view that protein kinase C is the only family of receptors for phorbol esters. This proposal was designed to investigate the biological functions of chimaerins. We found that 1 the mRNA levels of beta2-chimaerin, one of the most widely expressed chimaerin isoforms, were significantly lower in breast cancer cells and tissues than that in breast normal cells and tissues 2 re-expression of beta2-chimaerin or its catalytical domain beta-GAP using an adenoviral gene delivery technique induced cell cycle arrest at G1 phase and subsequently inhibited breast cancer cell proliferation 3 the effect of beta2- chimaerin on cell cycle progression and cell proliferation entirely depended on its Rac-GAP activity 4 heregulin beta1 HRG, an EGF-like growth factor and a mitogen for breast cancer cells, is a strong activator of Rac in breast cancer cells and promotes breast cancer cell proliferation through ErbB receptorsPI3KRacErk-dependent up-regulation of cyclin D1 and p21 expression 5 expression of beta2-chimaerin inhibited HRG-induced Rac activation and impaired Rac-dependent responses including cell migration, Erk12 activation, cyclin D1 and p21 expression, and cell proliferation. These findings suggest that beta2-chimaerin may act as a tumor suppressor.
- Anatomy and Physiology
- Medicine and Medical Research