Transcriptional element H4‐site II of cell cycle regulated human H4 histone genes is a multipartite protein/DNA interaction site for factors HiNF‐D, HiNF‐M, and HiNF‐P: Involvement of phosphorylation

Andre J. van Wijnen, Anna L. Ramsey‐Ewing, Rita Bortell, Thomas A. Owen, Jane B. Lian, Janet L. Stein, Gary S. Stein

Research output: Contribution to journalArticle

51 Scopus citations

Abstract

Cell cycle regulated gene expression was studied by analyzing protein/DNA interactions occurring at the H4‐Site II transcriptional element of H4 histone genes using several approaches. We show that this key proximal promoter element interacts with at least three distinct sequence‐specific DNA binding activities, designated HiNF‐D, HiNF‐M, and HiNF‐P. HiNF‐D binds to an extended series of nucleotides, whereas HiNF‐M and HiNF‐P recognize sequences internal to the HiNF‐D binding domain. Gel retardation assays show that HiNF‐D and HiNF‐M each are represented by two distinct protein/DNA complexes involving the same DNA binding activity. These results suggest that these factors are subject to post‐translational modifications. Dephosphorylation experiments in vitro suggest that both electrophoretic mobility and DNA binding activities of HiNF‐D and HiNF‐M are sensitive to phosphatase activity. We deduce that these factors may require a basal level of phosphorylation for sequence specific binding to H4‐Site II and may represent phosphoproteins occurring in putative hyper‐ and hypo‐phosphorylated forms. Based on dramatic fluctuations in the ratio of the two distinct HiNF‐D species both during hepatic development and the cell cycle in normal diploid cells, we postulate that this modification of HiNF‐D is related to the cell cycle. However, in several tumor‐derived and transformed cell types the putative hyperphosphorylated form of HiNF‐D is constitutively present. These data suggest that deregulation of a phosphatase‐sensitive post‐translational modification required for HiNF‐D binding is a molecular event that reflects abrogation of a mechanism controlling cell proliferation. Thus, phosphorylation and dephosphosphorylation of histone promoter factors may provide a basis for modulation of protein/DNA interactions and H4 histone gene transcription during the cell cycle and at the onset of quiescence and differentiation.

Original languageEnglish (US)
Pages (from-to)174-189
Number of pages16
JournalJournal of cellular biochemistry
Volume46
Issue number2
DOIs
StatePublished - Jun 1991

Keywords

  • cell cycle
  • development
  • histone
  • phosphorylation
  • proliferation
  • transcription

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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