Phosphorylation mediates Sp1 coupled activities of proteolytic processing, desumoylation and degradation

Mary L. Spengler, Li Wu Guo, Michael G. Brattain

Research output: Contribution to journalArticle

25 Scopus citations

Abstract

Cell signaling pathways induce Sp1 phosphorylation, which allows for the upregulation of Sp1-dependent genes that control cell growth, cell cycle progression, survival and tumorigenesis. Sp1 activity is under constitutive repression through the sumoylation of Lysine-16, and Lysine-16 dependent N-terminal cleavage relieves this repression. The present investigation probes further into the mechanisms of Sp1 processing, desumoylation and degradation to reveal that phosphorylation is the major driving force behind these coupled activities. The first 7 amino acid residues of Sp1 enhance the accessibility of Lysine-16 to the homologous modifiers SUMO-1 and ubiquitin; and Serine-7 specifically enhances ubiquitinylation. Our data show that Serine-59 regulates Sp1 proteolytic processing, and thereby provides a mechanism for the upregulation of Sp1-dependent transcription by CyclinA/cdk2 phosphorylation of Serine-59. Sp1 activators, forskolin and PMA, enhance Sp1 processing in MCFE cells through distinct signaling pathways. PKC, ERK and ERBB2 kinase inhibitors suppress PMA induction of Sp1 and the specific isozyme PKCα enhances Sp1 cleavage. Sp1 contains several NF?B2-like proteolytic processing components including a functional phosphorylation-dependent β-TrCP binding motif. From these data, we propose a model by which cell cycle and mitotic kinases induce Sp1 proteolytic processing resulting in a desumoylated, derepressed and unstable Sp1 product.

Original languageEnglish (US)
Pages (from-to)623-630
Number of pages8
JournalCell Cycle
Volume7
Issue number5
DOIs
StatePublished - Mar 1 2008

Keywords

  • Degradation
  • Key regulatory lysine
  • Phosphorylation
  • Proteolytic processing
  • Sp1
  • Sumoylation
  • Transcriptional regulation
  • Ubiquitinylation

ASJC Scopus subject areas

  • Molecular Biology
  • Developmental Biology
  • Cell Biology

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