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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM044634-08
Application #
6018803
Study Section
Cellular Biology and Physiology Subcommittee 1 (CBY)
Project Start
1991-05-01
Project End
2001-06-30
Budget Start
1999-07-01
Budget End
2000-06-30
Support Year
8
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Tufts University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
604483045
City
Boston
State
MA
Country
United States
Zip Code
02111
Berasi, Stephen P; Xiu, Mei; Yee, Amy S et al. (2004) HBP1 repression of the p47phox gene: cell cycle regulation via the NADPH oxidase. Mol Cell Biol 24:3011-24
Yee, Amy S; Paulson, Eric K; McDevitt, Michael A et al. (2004) The HBP1 transcriptional repressor and the p38 MAP kinase: unlikely partners in G1 regulation and tumor suppression. Gene 336:1-13
Xiu, Mei; Kim, Jiyoung; Sampson, Ellen et al. (2003) The transcriptional repressor HBP1 is a target of the p38 mitogen-activated protein kinase pathway in cell cycle regulation. Mol Cell Biol 23:8890-901
Hassan, Waleed N; Cantuti-Castelevetri, Ippolita; Denisova, Natalia A et al. (2002) The nitrone spin trap PBN alters the cellular response to H(2)O(2): activation of the EGF receptor/ERK pathway. Free Radic Biol Med 32:551-61
Sampson, E M; Haque, Z K; Ku, M C et al. (2001) Negative regulation of the Wnt-beta-catenin pathway by the transcriptional repressor HBP1. EMBO J 20:4500-11
Shih, H H; Xiu, M; Berasi, S P et al. (2001) HMG box transcriptional repressor HBP1 maintains a proliferation barrier in differentiated liver tissue. Mol Cell Biol 21:5723-32
Yee, A S; Shih, H H; Tevosian, S G (1998) New perspectives on retinoblastoma family functions in differentiation. Front Biosci 3:D532-47
Gartel, A L; Goufman, E; Tevosian, S G et al. (1998) Activation and repression of p21(WAF1/CIP1) transcription by RB binding proteins. Oncogene 17:3463-9
Shih, H H; Tevosian, S G; Yee, A S (1998) Regulation of differentiation by HBP1, a target of the retinoblastoma protein. Mol Cell Biol 18:4732-43
Tevosian, S G; Shih, H H; Mendelson, K G et al. (1997) HBP1: a HMG box transcriptional repressor that is targeted by the retinoblastoma family. Genes Dev 11:383-96

Showing the most recent 10 out of 15 publications