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p16 inhibits matrix metalloproteinase-2 expression via suppression of Sp1-mediated gene transcription

Chie-Hong Wang1, Hui-Chiu Chang, Wen-Chun Hung

  • 1Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan.

Journal of Cellular Physiology
|April 1, 2006
PubMed

Insights

The tumor suppressor p16 inhibits matrix metalloproteinase-2 (MMP-2) by blocking Sp1 transcription factor binding to the MMP-2 promoter, thus reducing cancer cell invasion and metastasis.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Biochemistry

Background:

  • p16, a cyclin-dependent kinase inhibitor and tumor suppressor, is implicated in inhibiting matrix metalloproteinase-2 (MMP-2) expression.
  • The precise molecular mechanisms by which p16 suppresses MMP-2 in human cancer cells remain incompletely understood.

Purpose of the Study:

  • To elucidate the detailed mechanism by which p16 inhibits MMP-2 expression.
  • To investigate the role of Sp1 transcription factor and its interaction with p16 in regulating MMP-2 transcription.

Main Methods:

  • Promoter deletion and mutation analysis of the human MMP-2 promoter.
  • DNA affinity precipitation assay (DAPA) and chromatin immunoprecipitation (CHIP) assays.
  • Investigation of the interaction between p16, Sp1, cyclin A, and CDK2.

Main Results:

  • p16 represses MMP-2 gene expression transcriptionally by targeting an Sp1 binding site (-72 to -64 bp) on the MMP-2 promoter.
  • p16 attenuates Sp1 binding to the MMP-2 promoter, an effect counteracted by Sp1 overexpression.
  • p16 downregulates cyclin A and CDK2, reducing Sp1 phosphorylation and DNA-binding activity.

Conclusions:

  • p16 suppresses MMP-2 expression and subsequent tumor invasion/metastasis by inhibiting Sp1-mediated gene transcription.
  • The p16-mediated suppression of MMP-2 involves the downregulation of cyclin A/CDK2, leading to reduced Sp1 activity.

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