Wnt induction of chondrocyte hypertrophy through the Runx2 transcription factor

Dong, Yufeng; Soung, Do Y.; Schwarz, Edward M.; O’Keefe, Regis J.; Drissi, Hicham

doi:10.1002/jcp.20656

Cited by 211 publications

(180 citation statements)

References 55 publications

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“…In addition, Qiao et al (2004) reported that IGF-1 stimulates the activity of the transcription factor RUNX2, through a PI3K-dependent but Akt-independent signaling pathway. Both Fra-1 and Runx2 are known downstream targets of the Wnt or cat/TCF signaling pathway (Mann et al, 1999;Dong et al, 2006). In this study, we found that insulin stimulates PAK-1 phosphorylation/activation in multiple cancer cell lines and in mouse intestinal tissues on Thr423, a target residue of phosphoinositide-dependent kinase isozyme-1, hence bypassing Akt (King et al, 2000).…”

Section: Discussionmentioning

confidence: 63%

P-21-activated protein kinase-1 functions as a linker between insulin and Wnt signaling pathways in the intestine

et al. 2009

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Hyperinsulinemia and type II diabetes are associated with an increased risk of developing colorectal tumors. We found previously that in intestinal cells, insulin or insulinlike growth factor-1 stimulates c-Myc and cyclin D1 protein expression through both Akt-dependent and Aktindependent mechanisms. The effect of Akt is attributed to the stimulation of c-Myc translation by mammalian target of rapamycin. However, Akt-independent stimulation was, associated with an increase in b-catenin (b-cat) in the nucleus and an increased association between b-cat and T-cell factor binding sites on the c-Myc promoter, detected by chromatin immunoprecipitation. In this study, we show that insulin stimulated the phosphorylation/ activation of p-21-activated protein kinase-1 (PAK-1) in an Akt-independent manner in vitro and in an in vivo hyperinsulinemic mouse model. Significantly, shRNA (small hairpin RNA)-mediated PAK-1 knockdown attenuated both basal and insulin-stimulated c-Myc and cyclin D1 expression, associated with a marked reduction in extracellular signal-regulated kinase activation and b-cat phosphorylation at Ser675. Furthermore, PAK-1 silencing led to a complete blockade of insulin-stimulated b-cat binding to the c-Myc promoter and cellular growth. Finally, inhibition of MEK, a downstream target of PAK-1, blocked insulin-stimulated nuclear b-cat accumulation and c-Myc expression. Our observations suggest that PAK-1 serves as an important linker between insulin and Wnt signaling pathways.

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Section: Discussionmentioning

confidence: 63%

P-21-activated protein kinase-1 functions as a linker between insulin and Wnt signaling pathways in the intestine

et al. 2009

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“…(35,53) This mimics in some way the natural process of chondrocyte hypertrophy and osteogenesis. Seven days after application of BIO, the expression of SOX9 was decreased, and the expression of RUNX2 was prominently detected [although it was not expressed initially in the chondrocytes (day 3)] and compared with the DMSO control.…”

Section: Sox9 Enhances the Degradation Of Runx2 Through The Lysosomalmentioning

confidence: 96%

“…(1,10,31) Indeed, it has been found that SOX9 exerts a dominant function over RUNX2 in mesenchymal precursors. (32) RUNX2 regulates chondrocyte maturation and also chondrocyte hypertrophy, (33)(34)(35) which suggests that RUNX2 suppresses SOX9 at some stage during skeletal development. Here we determined the nature of RUNX2-SOX9 interactions and the mechanism by which SOX9 regulates RUNX2 function.…”

Section: Introductionmentioning

confidence: 99%

SOX9 determines RUNX2 transactivity by directing intracellular degradation

Cheng

Genever

2010

Journal of Bone and Mineral Research

133

112

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Mesenchymal stem cell differentiation is controlled by the cooperative activity of a network of signaling mechanisms. Among these, RUNX2 and SOX9 are the major transcription factors for osteogenesis and chondrogenesis, respectively. Their expression is overlapped both temporally and spatially during embryogenesis. Here we have demonstrated that RUNX2 and SOX9 physically interact in intact cells and have confirmed that SOX9 can inhibit the transactivation of RUNX2. In addition, RUNX2 exerts reciprocal inhibition on SOX9 transactivity. In analyses of the mechanism by which SOX9 regulated RUNX2 function, we demonstrated that SOX9 induced a dosedependent degradation of RUNX2. Although RUNX2 is normally degraded by the ubiquitin-proteasome pathway, we found that SOX9-mediated degradation was proteasome-independent but phosphorylation-dependent and required the presence of the RUNX2 Cterminal domain, which contains a nuclear matrix targeting sequence (NMTS). Furthermore, SOX9 was able to decrease the level of ubiquitinated RUNX2 and direct RUNX2 to the lysosome for degradation. SOX9 also preferentially directed b-catenin, an intracellular mediator of canonical Wnt signaling, for lysosomal breakdown. Consequently, the mechanisms by which SOX9 regulates RUNX2 function may underlie broader signaling pathways that can influence osteochondrogenesis and mesenchymal fate. ß

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“…Treatment with TMP and stabilization of DD-ICAT resulted in downregulation of the β-catenin/TCF target genes Axin2, Enc1, Mecom, and Runx2 (Fig. 3D) (23,24,27,28), as well as down-regulation of a luciferase reporter driven by a 7× repeat of the canonical TCF binding sequence (Fig. 3E) (29).…”

Section: Myc-induced Lymphomas Exhibit Addiction To Mutant β-Cateninmentioning

confidence: 99%

Addiction to multiple oncogenes can be exploited to prevent the emergence of therapeutic resistance

Choi

Felsher

2014

Proc. Natl. Acad. Sci. U.S.A.

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Many cancers exhibit sensitivity to the inhibition of a single genetic lesion, a property that has been successfully exploited with oncogene-targeted therapeutics. However, inhibition of single oncogenes often fails to result in sustained tumor regression due to the emergence of therapy-resistant cells. Here, we report that MYC-driven lymphomas frequently acquire activating mutations in β-catenin, including a previously unreported mutation in a splice acceptor site. Tumors with these genetic lesions are highly dependent on β-catenin for their survival and the suppression of β-catenin resulted in marked apoptosis causally related to a decrease in Bcl-xL expression. Using a novel inducible inhibitor of β-catenin, we illustrate that, although MYC withdrawal or β-catenin inhibition alone results in initial tumor regression, most tumors ultimately recurred, mimicking the clinical response to single-agent targeted therapy. Importantly, the simultaneous combined inhibition of both MYC and β-catenin promoted more rapid tumor regression and successfully prevented tumor recurrence. Hence, we demonstrated that MYC-induced tumors are addicted to mutant β-catenin, and the combined inactivation of MYC and β-catenin induces sustained tumor regression. Our results provide a proof of principle that targeting multiple oncogene addicted pathways can prevent therapeutic resistance.oncogene addiction | combination targeted therapy | splice site mutations

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Wnt induction of chondrocyte hypertrophy through the Runx2 transcription factor

Cited by 211 publications

References 55 publications

P-21-activated protein kinase-1 functions as a linker between insulin and Wnt signaling pathways in the intestine

P-21-activated protein kinase-1 functions as a linker between insulin and Wnt signaling pathways in the intestine

SOX9 determines RUNX2 transactivity by directing intracellular degradation

Addiction to multiple oncogenes can be exploited to prevent the emergence of therapeutic resistance

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