mir-29 regulates Mcl-1 protein expression and apoptosis

J. L. Mott, S. Kobayashi, S. F. Bronk, Gregory James Gores

Research output: Contribution to journalArticle

633 Citations (Scopus)

Abstract

Cellular expression of Mcl-1, an anti-apoptotic Bcl-2 family member, is tightly regulated. Recently, Bcl-2 expression was shown to be regulated by microRNAs, small endogenous RNA molecules that regulate protein expression through sequence-specific interaction with messenger RNA. By analogy, we reasoned that Mcl-1 expression may also be regulated by microRNAs. We chose human immortalized, but non-malignant, H69 cholangiocyte and malignant KMCH cholangiocarcinoma cell lines for these studies, because Mcl-1 is dysregulated in cells with the malignant phenotype. By in silico analysis, we identified a putative target site in the Mcl-1 mRNA for the mir-29 family, and found that mir-29b was highly expressed in cholangiocytes. Interestingly, mir-29b was downregulated in malignant cells, consistent with Mcl-1 protein upregulation. Enforced mir-29b expression reduced Mcl-1 protein expression in KMCH cells. This effect was direct, as mir-29b negatively regulated the expression of an Mcl-1 3′ untranslated region (UTR)-based reporter construct. Enforced mir-29b expression reduced Mcl-1 cellular protein levels and sensitized the cancer cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) cytotoxicity. Transfection of non-malignant cells (that express high levels of mir-29) with a locked-nucleic acid antagonist of mir-29b increased Mcl-1 levels and reduced TRAIL-mediated apoptosis. Thus mir-29 is an endogenous regulator of Mcl-1 protein expression, and thereby, apoptosis.

Original languageEnglish (US)
Pages (from-to)6133-6140
Number of pages8
JournalOncogene
Volume26
Issue number42
DOIs
StatePublished - Sep 13 2007

Fingerprint

Apoptosis
Proteins
MicroRNAs
Messenger RNA
Cholangiocarcinoma
3' Untranslated Regions
Computer Simulation
Transfection
Up-Regulation
Down-Regulation
Tumor Necrosis Factor-alpha
RNA
Ligands
Phenotype
Cell Line
Neoplasms

Keywords

  • Apoptosis
  • Cholangiocarcinoma
  • microRNA
  • Post-transcriptional regulation
  • TRAIL

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

mir-29 regulates Mcl-1 protein expression and apoptosis. / Mott, J. L.; Kobayashi, S.; Bronk, S. F.; Gores, Gregory James.

In: Oncogene, Vol. 26, No. 42, 13.09.2007, p. 6133-6140.

Research output: Contribution to journalArticle

Mott, JL, Kobayashi, S, Bronk, SF & Gores, GJ 2007, 'mir-29 regulates Mcl-1 protein expression and apoptosis', Oncogene, vol. 26, no. 42, pp. 6133-6140. https://doi.org/10.1038/sj.onc.1210436
Mott, J. L. ; Kobayashi, S. ; Bronk, S. F. ; Gores, Gregory James. / mir-29 regulates Mcl-1 protein expression and apoptosis. In: Oncogene. 2007 ; Vol. 26, No. 42. pp. 6133-6140.
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