Author

David Piluso

Date of Award

8-2004

Degree Type

Thesis

Degree Name

Doctor of Philosophy (PhD)

Department

Biochemistry

Supervisor

Professor J.P. Capone

Abstract

HCF-l, a transcriptional regulatory protein, was originally identified as an accessory factor for the induction of Herpes Simplex Virus immediate-early genes by the viral transactivator VPl6. Recently, HCF-1 has emerged as a chromatin-binding transcriptional co-regulator that plays an essential role in cellular proliferation. In order to further characterize the function of HCF-l and determine the mechanisms by which it contributes to cellular proliferation we have sought to identify novel HCF-1 interaction partners and elucidate their function. In this thesis, we describe the identification of key cell cycle regulatory proteins, Miz-1 and E2F-4, as novel HCF-1 interaction partners. Miz-1, a transcription factor that activates transcription of cell cycle inhibitory genes, is an integral part of the anti-mitogenic TGF-β pathway and contributes to cell cycle arrest following DNA damage and differentiation signals. HCF-1 associates with the Miz-1 transactivation domain and antagonizes Miz-1- dependent transcriptional activation of p15INK4b, a cyclin-dependent kinase inhibitor, suggesting that HCF-1 can indirectly promote pRB family inactivation, and thus, cellular proliferation. E2F-4, a member of the E2F family of transcription factors that regulate cellular proliferation in conjunction with the retinoblastoma family of proteins, is involved in repression of E2F responsive genes at GO/G1 and consequently, cell cycle arrest or differentiation. Overexpression of E2F-4 suppresses HCF-1-mediated rescue of cellular proliferation, indicating an antagonistic role for these proteins in the cell cycle. Together, these findings contribute to identifying additional HCF-1 interaction partners and may provide insight into the molecular mechanism of HCF-1-mediated cell cycle progression.

Comments

HCF-l, a transcriptional regulatory protein, was originally identified as an accessory factor for the induction of Herpes Simplex Virus immediate-early genes by the viral transactivator VP16. Recently, HCF-1 has emerged as a chromatin-binding transcriptional co-regulator that plays an essential role in cellular proliferation. In order to further characterize the function of HCF-1 and determine the mechanisms by which it contributes to cellular proliferation we have sought to identify novel HCF-1 interaction partners and elucidate their function. In this thesis, we describe the identification of key cell cycle regulatory proteins, Miz-1 and E2F-4, as novel HCF-1 interaction partners. Miz-1, a transcription factor that activates transcription of cell cycle inhibitory genes, is an integral part of the anti-mitogenic TGF-β pathway and contributes to cell cycle arrest following DNA damage and differentiation signals. HCF-1 associates with the Miz-1 transactivation domain and antagonizes Miz-1-dependent transcriptional activation of p15INK4b, a cyclin-dependent kinase inhibitor, suggesting that HCF-1 can indirectly promote pRB family inactivation, and thus, cellular proliferation. E2F-4, a member of the E2F family of transcription factors that regulate cellular proliferation in conjunction with the retinoblastoma family of proteins, is involved in repression of E2F responsive genes at G0/G1 and consequently, cell cycle arrest or differentiation. Overexpression of E2F-4 suppresses HCF-1-mediated rescue of cellular proliferation, indicating an antagonistic role for these proteins in the cell cycle. Together, these findings contribute to identifying additional HCF-1 interaction partners and may provide insight into the molecular mechanism of HCF-1-mediated cell cycle progression.

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