The basic helix-loop-helix/Leucine zipper transcription factor USF2 integrates serum-induced PAI-1 expression and keratinocyte growth

Research output: Contribution to journalArticle

Authors

  • Li Qi
  • Craig E. Higgins
  • Stephen P. Higgins
  • Brian K. Law
  • Tessa M. Simone
  • Paul J. Higgins

External Institution(s)

  • Albany Medical College
  • University of Florida

Details

Original languageEnglish (US)
Pages (from-to)1840-1847
Number of pages8
JournalJournal of cellular biochemistry
Volume115
Issue number10
StatusPublished - Oct 2014
Peer-reviewedYes

Abstract

Plasminogen activator inhibitor type-1 (PAI-1), a major regulator of the plasmin-dependent pericellular proteolytic cascade, is prominently expressed during the tissue response to injury although the factors that impact PAI-1 induction and their role in the repair process are unclear. Kinetic modeling using established biomarkers of cell cycle transit (c-MYC; cyclin D1; cyclin A) in synchronized human (HaCaT) keratinocytes, and previous cytometric assessments, indicated that PAI-1 transcription occurred early after serum-stimulation of quiescent (G0) cells and prior to G1 entry. It was established previously that differential residence of USF family members (USF1→USF2 switch) at the PE2 region E box (CACGTG) characterized the G0 → G1 transition period and the transcriptional status of the PAI-1 gene. A consensus PE2 E box motif (5′-CACGTG-3′) at nucleotides -566 to -561 was required for USF/E box interactions and serum-dependent PAI-1 transcription. Site-directed CG → AT substitution at the two central nucleotides inhibited formation of USF/probe complexes and PAI-1 promoter-driven reporter expression. A dominant-negative USF (A-USF) construct or double-stranded PE2 "decoy" attenuated serum- and TGF-β1-stimulated PAI-1 synthesis. Tet-Off induction of an A-USF insert reduced both PAI-1 and PAI-2 transcripts while increasing the fraction of Ki-67+ cells. Conversely, overexpression of USF2 or adenoviral-delivery of a PAI-1 vector inhibited HaCaT colony expansion indicating that the USF1 → USF2 transition and subsequent PAI-1 transcription are critical events in the epithelial go-or-grow response. Collectively, these data suggest that USF2, and its target gene PAI-1, regulate serum-stimulated keratinocyte growth, and likely the cadence of cell cycle progression in replicatively competent cells as part of the injury repair program.

    Research areas

  • EXPRESSION PROFILING, GENE REGULATION, KERATINOCYTES, PAI-1, SERPINE1, TRANSCRIPTION, USF

Citation formats

APA

Qi, L., Higgins, C. E., Higgins, S. P., Law, B. K., Simone, T. M., & Higgins, P. J. (2014). The basic helix-loop-helix/Leucine zipper transcription factor USF2 integrates serum-induced PAI-1 expression and keratinocyte growth. Journal of cellular biochemistry, 115(10), 1840-1847. https://doi.org/10.1002/jcb.24861

Harvard

Qi, L, Higgins, CE, Higgins, SP, Law, BK, Simone, TM & Higgins, PJ 2014, 'The basic helix-loop-helix/Leucine zipper transcription factor USF2 integrates serum-induced PAI-1 expression and keratinocyte growth', Journal of cellular biochemistry, vol. 115, no. 10, pp. 1840-1847. https://doi.org/10.1002/jcb.24861