The overall goal of this project is to understand the function of HCF proteins in cell division and proliferatior. The founding member of this family is the human herpes simplex virus (HSV) host cell factor HCF-1. HCF(also known as Cl, VCAF, and CFF) is an abundant chromatin-associated protein that is highly conserved i animals. It is a large protein that undergoes an unusual maturation process involving proteolysis that results i N- and C-terminal HCF-1N and HCF-1c polypeptides that remain stably associated with one another. Dunn HSV infection, HCF-1 plays an important regulatory role in the transcription of HSV immediate-early (IE genes through its association with the HSV transactivator VP16. In uninfected cells, HCF-1 plays a critica role in cell division and proliferation through its association with chromatin. HCF- 1 does not association directly with DNA but associates with chromatin through a defined protein-protein interaction module, Keich domain, also used to tether HCF-1 to the HSV genome through its interaction with VP 16. HCF-1 and related human protein HCF-2 share a single conserved homolog in the worm Caenorhabditis elegans, called C. elegans HCF (CeHCF). Loss of HCF- 1 function in a mammalian cell line and CeHCF function in worm leads to similar defects in cytokinesis and mitotic histone phosphorylation - defects that suggest disruption o the Aurora B kinase-Protein Phosphatase 1 (PP1) pathway. At least some of the defects caused by loss o HCF-1 function can be overcome by inactivation of the pRb tumor suppressor, suggesting that a natural role o HCF-1 is to suppress pRb function, either directly or indirectly. Thus, HCF-1 appears to be a key regulator o cell proliferation. In this project, we will continue to use innovative and complementary genetic, molecula and cell biological, and biochemical approaches to dissect the structure and function of HCF proteins in thei critical roles in cell division and proliferation.
Our specific aims are (i) to study the roles of HCF-1 i mammalian-cell proliferation and differentiation; (ii) to identify and characterize the effectors of HCFfunction in mammalian cells; and to elucidate the roles of HCF-protein function in Caenorhabditis elegans.
|Tyagi, Shweta; Chabes, Anna Lena; Wysocka, Joanna et al. (2007) E2F activation of S phase promoters via association with HCF-1 and the MLL family of histone H3K4 methyltransferases. Mol Cell 27:107-19|
|Julien, Eric; Herr, Winship (2004) A switch in mitotic histone H4 lysine 20 methylation status is linked to M phase defects upon loss of HCF-1. Mol Cell 14:713-25|
|Yokoyama, Akihiko; Wang, Zhong; Wysocka, Joanna et al. (2004) Leukemia proto-oncoprotein MLL forms a SET1-like histone methyltransferase complex with menin to regulate Hox gene expression. Mol Cell Biol 24:5639-49|
|Julien, Eric; Herr, Winship (2003) Proteolytic processing is necessary to separate and ensure proper cell growth and cytokinesis functions of HCF-1. EMBO J 22:2360-9|
|Wysocka, Joanna; Myers, Michael P; Laherty, Carol D et al. (2003) Human Sin3 deacetylase and trithorax-related Set1/Ash2 histone H3-K4 methyltransferase are tethered together selectively by the cell-proliferation factor HCF-1. Genes Dev 17:896-911|
|Reilly, Patrick T; Herr, Winship (2002) Spontaneous reversion of tsBN67 cell proliferation and cytokinesis defects in the absence of HCF-1 function. Exp Cell Res 277:119-30|
|Reilly, Patrick T; Wysocka, Joanna; Herr, Winship (2002) Inactivation of the retinoblastoma protein family can bypass the HCF-1 defect in tsBN67 cell proliferation and cytokinesis. Mol Cell Biol 22:6767-78|
|Wysocka, J; Reilly, P T; Herr, W (2001) Loss of HCF-1-chromatin association precedes temperature-induced growth arrest of tsBN67 cells. Mol Cell Biol 21:3820-9|
|Lee, S; Herr, W (2001) Stabilization but not the transcriptional activity of herpes simplex virus VP16-induced complexes is evolutionarily conserved among HCF family members. J Virol 75:12402-11|
|Wysocka, J; Liu, Y; Kobayashi, R et al. (2001) Developmental and cell-cycle regulation of Caenorhabditis elegans HCF phosphorylation. Biochemistry 40:5786-94|
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