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Intracellular MMP3 Promotes HSP Gene Expression in Collaboration With Chromobox Proteins

Takanori Eguchi1,2,3,4, Stuart K Calderwood1, Masaharu Takigawa3

  • 1Department of Radiation Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, 02115, Massachusetts.

Journal of Cellular Biochemistry
|May 22, 2016
PubMed

Insights

Intracellular matrix metalloproteinase 3 (MMP3) activates heat shock protein (HSP) gene transcription. MMP3, along with heat shock factor 1 and chromobox proteins, promotes HSP gene expression within the cell nucleus.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Matrix metalloproteinases (MMPs) are key regulators of tumor progression, inflammation, and tissue repair.
  • Previous research established that MMP3 can enter the cell nucleus and influence gene transcription.
  • The specific transcriptional targets and cofactors of nuclear MMP3 remained largely unknown.

Purpose of the Study:

  • To identify novel transcriptional target genes regulated by intracellular MMP3.
  • To elucidate the molecular mechanisms and cofactors involved in MMP3-mediated gene regulation within the nucleus.

Main Methods:

  • Transcriptomics analysis was employed to identify genes upregulated by intracellular MMP3.
  • Bioinformatic analysis predicted potential transcription factor interactions with MMP3.
  • Reporter gene assays and dominant-negative constructs were used to validate cofactor roles.
  • Specific domains of MMP3 and interacting proteins were assessed for their role in gene induction.

Main Results:

  • Intracellular MMP3 overload led to the upregulation of heat shock protein (HSP) family members, including HSP70B', HSP72, HSP40/DNAJ, and HSP20/CRYAB.
  • Heat shock factor 1 (HSF1) was identified as a cooperating factor with MMP3 in activating the HSP70B' gene promoter.
  • The hemopexin-like repeat (PEX) domain of MMP3 was crucial for transcriptional induction of HSP70B'.
  • Chromobox proteins CBX5/HP1α and CBX3/HP1γ were found to cooperate with the PEX domain in inducing HSP70B' mRNA.

Conclusions:

  • Intracellular MMP3 plays a significant role in the transcriptional regulation of HSP genes.
  • MMP3 cooperates with HSF1, CBX5/HP1α, and CBX3/HP1γ to promote HSP gene expression.
  • The PEX domain of MMP3 is essential for this nuclear transcriptional activity.
Keywords:
CBXsCHROMOBOX PROTEINSHEAT SHOCK FACTOR 1HEAT SHOCK PROTEINSHETEROCHROMATIN PROTEINSHP1HSF1HSPsMATRIX METALLOPROTEINASEMMP3TRANSCRIPTION

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