Cell Cycle Analysis in Multi-step Tumorigenesis
The p27kip1 protein, a member of the Cip/Kip family of cyclin dependent kinase inhibitors, is deregulated in many human cancers and functions as a tumor suppressor in mice. Although the cell cycle inhibitory functions of p27kip1 are well characterized, the pathways of p27kip tumor suppression are not known. The goal of this interdisciplinary project is to identify the mechanisms through which p27kip1 functions as a tumor suppressor and to study these pathways in human tumor specimens. In order to identify oncogenic pathways associated with p27 loss, I am using the technique of retroviral mediated insertional mutagenesis. We have observed that murine leukemia-virus induced lymphomagenesis is greatly accelerated in p27-null animals. I am currently using molecular methods to identify the genes that are retrovirally activated in these p27-null tumors. Once identified, I will study these genes in human breast tumor specimens and correlate their patterns of expression with p27, other markers of tumor progression, and patient survival indices. Dr. Clurman's laboratory provides expertise in using molecular and animal model based methods to examine p27 deregulation while Dr. Porter's laboratory provides expertise in studying cell cycle related genes in human tumor specimens. The combined expertise of these two laboratories provides an ideal interdisciplinary environment to identify and examine the pathways by which deregulated p27kip is involved in human cancer.