Cyclin dependent kinases (Cdks) and their Cyclin partners are the positive regulators while the Cyclin-dependent kinase inhibitors (CKIs) are important negative regulators. Our research goals are to characterize the regulatory mechanism of cell cycle proliferation and identify the roles of CKIs in cell cycle regulations and cancer formation.

We have investigated whether there is a link between HER-2/neu oncogenic signals and p27 Kip1, a CKI, regulation in breast cancer by assessing the immunocytochemical staining pattern of p27 in the normal and neoplastic breast tissues. We showed that immunohistochemical screening of breast cancer samples revealed that downregulation of p27 correlated with HER-2/neu overexpression for promoting breast cancer formation. To address the molecular mechanism of this inverse correlation, we found that reduction of p27 is caused by enhanced ubiquitin-mediated degradation, and the HER-2/Grb2/MAPK pathway is involved in the decrease of p27 stability. Also, HER-2/neu activity causes mislocation of p27 and JAB1, an exporter of p27, into the cytoplasm, thereby facilitating p27 degradation. These results reveal that HER-2/neu signals reduce p27 stability and thus present potential points for therapeutic intervention in HER-2/neu associated cancers.

In addition, we have identified 14-3-3 sigma as a new class of CKI. 14-3-3 sigma, implicated in cell cycle arrest by p53, was cloned by expression cloning through Cdk2 association. 14-3-3 sigma shares cyclin-Cdk2 binding motifs with different cell cycle regulators, including p107, p130, p21 Cip1, p27 Kip1, and p57Kip2 and is associated with cyclin-Cdk complexes in vitro and in vivo. Overexpression of 14-3-3 sigma obstructs cell cycle entry by inhibiting cyclin-Cdk activity in many breast cancer cell lines. Overexpression of 14-3-3 sigma can also inhibit cell proliferation and prevent anchorage-independent growth of these cell lines. These findings define 14-3-3 sigma as a negative regulator of the cell cycle progression. We recently showed that 14-3-3 sigma positively regulate tumor suppressor p53, suggesting that it has an important function in preventing tumor cell growth.

A tutorial in this lab would offer research experience in both cell biology and molecular biology. Aspects of cell cycle regulation and their involvement in cancer formation will be emphasized. Molecular biology and cell biology techniques will be taught and introduced, including PCR, expression cloning, differential display, FACS, fluorescence microscopy, and in situ hybridization.

Recent publications