The mechanisms underlying cell cycle arrest and exit are critical to normal terminal differentiation and aberrant tumorigenesis pathways. The retinoblastoma (RB) family of growth suppressors are integral members of cell growth control pathways. While the role of the retinoblastoma family in G1/S control has been well-established, their role in complete cell cycle exit and terminal differentiation is not well-understood. To this end, we have isolated HBP-1, a new sequence specific HMG transcription factor, as a specific interactor of the RB family in differentiated cells. Our functional studies indicate that HBP-1 fit the criteria of a critical player in cell cycle arrest and exit pathways. First, the expression of HBP-1 in cells leads to efficient cell cycle arrest. HBP-1 levels are up- regulated in terminal differentiation, which is characterized by irreversible cell cycle exit. Second, HBP-1 functions as a transcriptional repressor of the N-MYC oncogene, whose role in organogenesis and tumorigenesis is well-established. Intriguingly, the N-MYC promoter is also regulated by the E2F transcription factors, a known G1/S regulator. Taken together, we propose that HBP-1 and E2F-1 constitute two important transcriptional regulators of cell cycle transitions and that these diverse signals can be integrated through the MYC promoter. The focus of this proposal are the molecular mechanisms of cell cycle control and transcriptional repression. The identification of a transcriptional repressor as an RB family target is also unique, as most previous transcriptional targets such as E2F have been activators. Because HBP-l can apparently execute both functions, understanding the cellular and molecular mechanisms may provide unique insights into both cell cycle best and exit and into transcriptional repression. The mechanisms of transcriptional repression are not well-understood, but may be as important as transcriptional activation in dictating patterns of gene expression. The mechanisms of cell cycle arrest and exit are also critical in oncogenesis. Elucidation of the molecular mechanism of this pathway may provide fundamental knowledge for the eventual development of therapeutic agents to treat aggressively proliferating tumors in which the irreversible cell cycle exit associated with normal tissue function has been overridden.
Showing the most recent 10 out of 15 publications
