Mutations in host cell factor 1 separate its role in cell proliferation from recruitment of VP16 and LZIP.
Host cell factor 1 (HCF-1) is a nuclear protein required for progression through G(1) phase of the cell cycle and, via its association with VP16, transcriptional activation of the herpes simplex virus immediate-early genes. Both functions require a six-bladed beta-propeller domain encoded by residues 1 to 380 of HCF-1 as well as an additional amino-terminal region. The beta-propeller domain is well conserved in HCF homologues, consistent with a critical cellular function. To date, the only known cellular target of the beta-propeller is a bZIP transcription factor known as LZIP or Luman. Whether the interaction between HCF-1 and LZIP is required for cell proliferation remains to be determined. In this study, we used directed mutations to show that all six blades of the HCF-1 beta-propeller contribute to VP16-induced complex assembly, association with LZIP, and cell cycle progression. Although LZIP and VP16 share a common tetrapeptide HCF-binding motif, our results reveal profound differences in their interaction with HCF-1. Importantly, with several of the mutants we observe a poor correlation between the ability to associate with LZIP and promote cell proliferation in the context of the full HCF-1 amino terminus, arguing that the HCF-1 beta-propeller domain must target other cellular transcription factors in order to contribute to G(1) progression.
Mahajan
S S
SS
Department of Microbiology, Kaplan Comprehensive Cancer Center, New York University School of Medicine, New York, New York 10016, USA.
Wilson
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AC
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D002453:Cell Cycle / Q000502:physiology*; D002455:Cell Division; D002460:Cell Line; D017362:Cyclic AMP Response Element-Binding Protein; D016193:G1 Phase; D017405:Herpes Simplex Virus Protein Vmw65 / Q000378:metabolism*; D051863:Host Cell Factor C1; D006801:Humans; D016350:Leucine Zippers; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D017433:Protein Structure, Secondary; D011506:Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D020449:Repetitive Sequences, Amino Acid; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D018139:Simplexvirus / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*; D014162:Transfection
C107941:CREB3 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; C497692:HCFC1 protein, human; D017405:Herpes Simplex Virus Protein Vmw65; D051863:Host Cell Factor C1; D011506:Proteins; D011994:Recombinant Proteins; D014157:Transcription Factors