Identification of New Substrates for Breast Tumor Specific LMW Cyclin E/CDK2 Kinase.

摘要

Cyclin E overexpression occurs in 25% of breast cancer tumors and is linked to poor prognosis. In tumor cells full length cyclin E (FL-E) is processed by an elastase-like protease into low-molecular weight isoforms (LMW-E) that are biochemically hyperactive. We recently demonstrated in a transgenic mouse model that CDK2 is required for LMW-E-induced breast cancer. The hypothesis is that the biological and biochemical differences between FL-E and LMW-E may be due to the phosphorylation of a distinct set of substrates when complexed with CDK2. The Protoarray analysis led us to discover Hbo1 and CINP as novel substrates of the LMW-E/CDK2 complex that may mediate critical downstream signaling to contribute to the oncogenic potential of LMW-E in breast cancer. We will pursue the identification of new substrates by phosphorylating a cell lysate in vitro with cyclin EL/CDK2 (F80G) and cyclin ELMW/ CDK2 (F80G) and PE-ATP-(gamma)-S. The identification of new physiological LMW-E/CDK2 substrates will lead to the development of novel targets for therapeutics and the identification of the biological function for the treatment of the aggressive LMW-E expressing triple negative breast cancer.