MicroRNA-34c inversely couples the biological functions of the runt-related transcription factor RUNX2 and the tumor suppressor p53 in osteosarcoma
Department of Cell and Developmental Biology
Medical Subject Headings
Animals; Bone Neoplasms; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Core Binding Factor Alpha 1 Subunit; Cyclin-Dependent Kinase Inhibitor p21; DNA Damage; Down-Regulation; Gamma Rays; Gene Expression Regulation, Neoplastic; Humans; Mice; MicroRNAs; Osteosarcoma; Protein Stability; RNA, Messenger; Tumor Suppressor Protein p14ARF; Tumor Suppressor Protein p53
Biochemistry | Cancer Biology | Cell Biology | Molecular Genetics
Osteosarcoma (OS) is a primary bone tumor that is most prevalent during adolescence. RUNX2, which stimulates differentiation and suppresses proliferation of osteoblasts, is deregulated in OS. Here, we define pathological roles of RUNX2 in the etiology of OS and mechanisms by which RUNX2 expression is stimulated. RUNX2 is often highly expressed in human OS biopsies and cell lines. Small interference RNA-mediated depletion of RUNX2 inhibits growth of U2OS OS cells. RUNX2 levels are inversely linked to loss of p53 (which predisposes to OS) in distinct OS cell lines and osteoblasts. RUNX2 protein levels decrease upon stabilization of p53 with the MDM2 inhibitor Nutlin-3. Elevated RUNX2 protein expression is post-transcriptionally regulated and directly linked to diminished expression of several validated RUNX2 targeting microRNAs in human OS cells compared with mesenchymal progenitor cells. The p53-dependent miR-34c is the most significantly down-regulated RUNX2 targeting microRNAs in OS. Exogenous supplementation of miR-34c markedly decreases RUNX2 protein levels, whereas 3'-UTR reporter assays establish RUNX2 as a direct target of miR-34c in OS cells. Importantly, Nutlin-3-mediated stabilization of p53 increases expression of miR-34c and decreases RUNX2. Thus, a novel p53-miR-34c-RUNX2 network controls cell growth of osseous cells and is compromised in OS.
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Citation: van der Deen M, Taipaleenmäki H, Zhang Y, Teplyuk NM, Gupta A, Cinghu S, Shogren K, Maran A, Yaszemski MJ, Ling L, Cool SM, Leong DT, Dierkes C, Zustin J, Salto-Tellez M, Ito Y, Bae SC, Zielenska M, Squire JA, Lian JB, Stein JL, Zambetti GP, Jones SN, Galindo M, Hesse E, Stein GS, van Wijnen AJ. MicroRNA-34c inversely couples the biological functions of the runt-related transcription factor RUNX2 and the tumor suppressor p53 in osteosarcoma. J Biol Chem. 2013 Jul 19;288(29):21307-19. doi: 10.1074/jbc.M112.445890. Link to article on publisher's site
Van der Deen, Margaretha; Taipaleenmaki, Hanna; Zhang, Ying; Teplyuk, Nadiya M.; Gupta, Anurag; Cinghu, Senthilkumar; Shogren, Kristen; Maran, Avudaiappan; Yaszemski, Michael J.; Ling, Ling; Cool, Simon M.; Leong, David Tai; Dierkes, Christian; Zustin, Jozef; Salto-Tellez, Manuel; Ito, Yoshiaki; Bae, Suk-Chul; Zielenska, Maria; Squire, Jeremy A.; Lian, Jane B.; Stein, Janet L.; Zambetti, Gerard P.; Jones, Stephen N.; Galindo, Mario; Hesse, Eric; Stein, Gary S.; and van Wijnen, Andre J., "MicroRNA-34c inversely couples the biological functions of the runt-related transcription factor RUNX2 and the tumor suppressor p53 in osteosarcoma" (2013). Stephen Jones Lab Publications. 30.