HCF-1 functions as a coactivator for the zinc finger protein Krox20.
HCF-1 is a transcriptional cofactor required for activation of herpes simplex virus immediate-early genes by VP16 as well as less clearly defined roles in cell proliferation, cytokinesis, and spliceosome formation. It is expressed as a large precursor that undergoes proteolysis to yield two subunits that remain stably associated. VP16 uses a degenerate 4-amino acid sequence, known as the HCF-binding motif, to bind to a six-bladed beta-propeller domain at the N terminus of HCF-1. Functional HCF-binding motifs are also found in LZIP and Zhangfei, two cellular bZIP transcription factors of unknown function. Here we show that the HCF-binding motif occurs in a wide spectrum of DNA-binding proteins and transcriptional cofactors. Three well characterized examples were further analyzed for their ability to use HCF-1 as a coactivator. Krox20, a zinc finger transcription factor required for Schwann cell differentiation, and E2F4, a cell cycle regulator, showed a strong requirement for functional HCF-1 to activate transcription. In contrast, activation by estrogen receptor-alpha did not display HCF dependence. In Krox20, the HCF-binding motif lies within the N-terminal activation domain and mutation of this sequence diminishes both transactivation and association with the HCF-1 beta-propeller. The activation domain in the C-terminal subunit of HCF-1 contributes to activation by Krox20, possibly through recruitment of p300. These results suggest that HCF-1 is recruited by many different classes of cellular transcription factors and is therefore likely to be required for a variety of cellular processes including cell cycle progression and development.
Luciano
Randy L
RL
Department of Microbiology and New York University Cancer Institute, New York University School of Medicine, New York, New York 10016, USA.
Wilson
Angus C
AC
D020816:Amino Acid Motifs; D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D016384:Consensus Sequence; D004268:DNA-Binding Proteins / Q000378:metabolism / Q000502:physiology*; D050704:E2F4 Transcription Factor; D051767:Early Growth Response Protein 2; D047628:Estrogen Receptor alpha; D051863:Host Cell Factor C1; D006801:Humans; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D051381:Rats; D011960:Receptors, Estrogen / Q000378:metabolism / Q000502:physiology; D013696:Temperature; D014157:Transcription Factors / Q000378:metabolism / Q000502:physiology*; D014162:Transfection; D016335:Zinc Fingers
D004268:DNA-Binding Proteins; D050704:E2F4 Transcription Factor; C497326:EGR2 protein, human; D051767:Early Growth Response Protein 2; C497328:Egr2 protein, rat; D047628:Estrogen Receptor alpha; C497692:HCFC1 protein, human; D051863:Host Cell Factor C1; D011960:Receptors, Estrogen; D014157:Transcription Factors