mir-29 regulates Mcl-1 protein expression and apoptosis.

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.

• Authors: J L Mott, S Kobayashi, S F Bronk, G J Gores
• Journal: Oncogene (Oncogene) Vol. 26 Issue 42 Pg. 6133-40 (Sep 13 2007) ISSN: 0950-9232 [Print] England
• PMID: 17404574 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• MicroRNAs
• Myeloid Cell Leukemia Sequence 1 Protein
• Neoplasm Proteins
• Proto-Oncogene Proteins c-bcl-2

Topics

• Apoptosis (genetics)
• Cell Line, Transformed
• Cell Line, Tumor
• Gene Expression Regulation, Neoplastic (physiology)
• Humans
• MicroRNAs (physiology)
• Myeloid Cell Leukemia Sequence 1 Protein
• Neoplasm Proteins (antagonists & inhibitors, biosynthesis, genetics)
• Proto-Oncogene Proteins c-bcl-2 (antagonists & inhibitors, biosynthesis, genetics)