An important theme in current cell cycle research is understanding how cell cycle regulatory proteins respond to mitogenic stimuli. A normal cell cycle always contains a period of mitogen dependence, which usually occupies the first few hours after each mitosis. If the requisite mitogenic signals are not received during this time, the cell will withdraw transiently into a quiescent state or sometimes more permanently undergo a post-mitotic arrest. However, once this mitogen-sensitive period ends the cellenters an autonomous state where the remaining events of the division cycle, including DNA replication and mitosis, occur independently of extracellular stimuli. In this way, each cell cycle is organized into alternating states of responsiveness and nonresponsiveness to environmental signals. The switch between these states reflects a point of commitment to complete one division cycle, and therefore represents the primary proliferative decision of the cell.
It is currently thought that mitogenic signals ultimately effect cell proliferation by modulating the activities of the proteins which control progression through the cell cycle. A family of protein kinases, the cyclin-dependent kinases (CDKs), control transit through the mitogen-sensitive portion of the G1 phase of the cell cycle, and it has been shown that their activities are dependent on mitogenic stimuli. The catalytic activity of CDKs is regulated by two general mechanisms, protein phosphorylation and association with regulatory subunits. Thetwo kinds of CDK regulatory subunits are CDK activators (named cyclins) and CDK inhibitors (named CKIs). The cyclins are periodically expressed during the cell cycle and upon binding to a CDK induce structural rearrangements that are both necessary for CDK catalytic activity and also help to determine its substrate specificity. The CKIs work in opposition to the cyclins. They bind directly to CDKs or cyclin-CDK complexes and inhibit their protein kinase activity. The coordinate regulation of cyclins and CKIs determines in large part the effect of mitogenic or antimitogenic signaling on CDK activity, and thereby causes the cell cycle to either start or stop.
Our laboratory is now focused on understanding how the activities of the cyclins and the CKIs are regulated during the cell cycle and how these proteins cooperate to control the mitogen responsiveness of cells both in vivo and in vitro. Our studies include both normal and tumorigenic cells.
Copyright © 2003-2013 Molecular & Cellular Biology Program, University of Washington
Fred Hutchison Cancer Research Center | University of Washington
Institute for Systems Biology | Seattle Biomed