Most definitions of cancer stress deregulation of cell proliferation. Specifically, the regulation of the G1 switching mechanisms between quiescence and proliferation is defective in cancer cells, allowing them to continuously cycle under conditions insufficient for normal cell proliferation. Hence, the deranged expression and function of cell cycle regulatory proteins active in the G1 phase of the cell cycle may be one of the keys to oncogenesis. Cyclin E, a regulatory subunit of cyclin-dependent kinase-2 (cdk2), is thought to be rate limiting for the G1/S transition during the mammalian cell cycle. Previously, the investigator has shown severe quantitative and qualitative alterations in cyclin E protein expression in human mammary epithelial cell lines that also appear in surgical material obtained from patients with various malignancies. In this application the investigator provides preliminary results on the deregulation of cyclin E in breast cancer cells. The investigator shows that, while cyclin E is cell-cycle regulated in normal cells, it is present constitutively and in an active cdk2 complex in synchronized populations of breast cancer cells. The investigator also has identified two novel variant forms of cyclin E mRNA as detected by RT-PCR, which are ubiquitously detected in normal and tumor cells and tissues. These variant forms of cyclin E can give rise to an active cyclin/cdk2 complex in vitro, but they do not seem to be translated in normal cells. The investigator's data strongly suggest that cyclin E is post-transcriptionally and/or translationally regulated, and that such regulation is lost or altered in tumor cells. To understand the functional basis of these alterations the investigator proposes to examine the mechanism of deregulation of cyclin E and identify the altered and lower-molecular-weight isoforms of cyclin E present exclusively in tumor cells; investigate the origin of these isoforms and why they are present only in tumor cells, decipher their biological activity and determine if they can be used therapeutically. The investigator believes that the studies outlined in this application will provide novel approaches for developing successful modes of detection and therapy for this disease.
| Chen, X; Lowe, M; Herliczek, T et al. (2000) Protection of normal proliferating cells against chemotherapy by staurosporine-mediated, selective, and reversible G(1) arrest. J Natl Cancer Inst 92:1999-2008 |
| Rao, S; Gray-Bablin, J; Herliczek, T W et al. (1999) The biphasic induction of p21 and p27 in breast cancer cells by modulators of cAMP is posttranscriptionally regulated and independent of the PKA pathway. Exp Cell Res 252:211-23 |
| Gray-Bablin, J; Rao, S; Keyomarsi, K (1997) Lovastatin induction of cyclin-dependent kinase inhibitors in human breast cells occurs in a cell cycle-independent fashion. Cancer Res 57:604-9 |
