Andrew Koff, PhD

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The appropriate control of DNA replication and subsequent cell division is required for development of an organism, and inappropriate control has a great impact in diseases such as cancer. There are 3 classes of proteins that negatively regulate entry into S-phase. These include members of the pocket-protein family -- Rb, p107, and p130 -- that act, in part, through regulating the E2F family of transcription factors. In addition, there are 2 classes of cdk inhibitor proteins: 4 of the Ink4-type (p15, p16, p18, and p19) that specifically target cyclin D-cdk4 and cdk6 activity, and 3 of the Cip-Kip type (p21, p27, and p57), which preferentially target cdk2 activity. Although we know that each of these proteins can impact to commit to the cell cycle, we really have very little understanding of their actions in a biologic system, and how changes in their function lead to tumors.

This laboratory approaches this complex problem by focusing on one of the proteins of the Cip/Kip class: p27. The reasons for this are historic, but have continually been justified by the findings over the last few years. First, in collaboration with Dr. Joan Massague's group, we identified this protein as a mediator of TGF-beta1 and contact inhibition-induced growth arrest in tissue culture cells. We showed that it interacted in a pathway linking mitogen-dependent activation of cyclin D-cdk4/6 to cyclin E-cdk2. Additionally, our studies on a p27-deficient mouse generated in our laboratory suggested that p27 was a major mediator of the growth-arrest response to differentiation-inducing signals in many cell types. Finally, the loss of p27 from human tumors of the colon, prostate, breast, lung, pituitary, esophagus, and bladder is associated with increased aggressiveness of the disease and poor prognosis.

The laboratory currently has efforts in 3 areas:

• the interactions of p27 with other proteins: specifically, are the Cip-Kips redundant in regulating growth arrest in differentiating cells? And how do they interact with the pocket-proteins?
• the development of a mouse model that mimics the prognostic significance of p27 in human disease; and
• the regulation of p27.

Each question is discussed in the appropriate subsection.