Cell-cycle control by protein kinase B

Abstract

Numerous cells in the body divide, and do so in a well-controlled manner. In some situations where this control is deregulated, cells may divide continuously. Such uncontrolled proliferation of cells is thought to be responsible for the onset of cancer. In order for a cell to divide in a normal setting, it requires stimuli from the body in the form of growth factors. These growth factors activate a cascade of protein-protein interactions in the cell that eventually lead to cell division. In tumors, certain of those proteins modified by growth factors are mutated, rendering them insensitive to the regulatory actions of growth factors. This can then lead to a constant divide signal . One of such proteins is PTEN, an enzyme that controls the action of protein kinase B (PKB), a protein that participates in the control of cell-death (apoptosis) and cell division. In many tumor cells, PKB is constitutively active. In this thesis, we investigated the molecular mechanism by which active PKB may contribute to uncontrolled proliferation. We find that PKB directly inhibits the actions of a Forkhead transcription factor, AFX, and furthermore that this AFX protein controls cellular proliferation by enhancing protein expression of a well-known cell-division inhibitor p27kip1. In this way, PKB, by decreasing AFX activity and thus the protein levels of p27kip1, can contribute to increased proliferation that may cause tumor formation.