THE CELL-CYCLE AND THE RETINOBLASTOMA PROTEIN FAMILY

Tumor formation results from alterations in the control of normal cell proliferation. To further our understanding of the molecular mechanisms underlying the deregulation of cell proliferation much attention, over the past decade, has been focused on the function of proto-oncogenes. Cellular oncogenes are thought to be growth promoting. More recently, a class of genes known as tumor suppressors have come under intense study. Tumor suppressors are largely thought to restrain cell proliferation. The retinoblastoma protein (Rb) is one of a growing list of tumor suppressors. Concurrent with the study of tumor suppressor genes has been a rapid increase in our understanding of the cell cycle at the molecular level. Rb and a related protein p107 are involved in the processes of cell proliferation and differentiation. Each functionally interacts with and affects the activity of the transcription factor E2F as well as other transcription factors involved in cell proliferation and differentiation. Additionally, Rb and p107 are modified by, and/or form specific complexes with, several elements of the basic cell cycle machinery. Specifically, Rb and p107 interact with and are modified by various cyclins and cyclin dependent kinases (cdk), some of which have been shown to be essential for cell cycle progression and in some cases their deregulation has been implicated in the development of cancer. This review will attempt to convey our current functional and mechanistic understanding of the biological roles Rb and p107 play in proliferation, development and differentiation. A knowledge of the interplay between these positive and negative regulators of cell proliferation and differentiation, noted above, is central to our understanding of human cancer.