Effect of Chimaerins, Novel Receptors for Phorbol Esters, on Breast Cancer Cell Proliferation and Cell Cycle Progression
Abstract
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 receptors/PI3K/Rac/Erk-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, Erk1/2 activation, cyclin D1 and p21 expression, and cell proliferation. These findings suggest that beta2-chimaerin may act as a tumor suppressor.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jul 01, 2006
- Accession Number
- ADA460064
Entities
People
- Chengfeng Yang
- Marcelo G Kazanietz
Organizations
- University of Pennsylvania