Runx2-mediated activation of the Bax gene increases osteosarcoma cell sensitivity to apoptosis

Ra, Eliseev; Yf, Dong; Sampson, Erik R.; Zuscik, Michael J.; Em, Schwarz; Rj, O'Keefe; Rn, Rosier; Drissi, Hicham

doi:10.1038/sj.onc.1211020

Cited by 61 publications

(61 citation statements)

References 40 publications

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“…Recent work has suggested that after treatment of SaOs-2 cells with BMPs, RUNX2 might directly activate the proapoptotic gene Bax (with no change in Bcl2 expression). (13) Our experiments in hMSCs gave similar results; in FCS-free medium, TNF-a induced a strong increase in Bax but did not modify Bcl-2 expression. When RUNX2 was inhibited by siRNA, no change in Bax expression was observed after TNF-a treatment.…”

Section: Discussionsupporting

confidence: 77%

“…It is also important to note the suggestion by Bellido and colleagues (45) that the antiapoptotic effects of parathyroid hormone (PTH) might require RUNX2-a position that appears to contradict the study by Eliseev and colleagues (13) and that work. However, these antiapoptotic effects are short-lived because PTH itself stimulates the proteasomal degradation of RUNX2.…”

Section: Discussionmentioning

confidence: 95%

“…(7) The involvement of RUNX2 as a regulator of osteoblast proliferation also was consistent with data obtained in other biologic contexts. (8)(9)(10)(11) More recently, Zaidi and colleagues (12) proposed that RUNX2 functions as a tumor suppressor in primary diploid osteoblasts, whereas Eliseev and colleagues (13) suggested that RUNX2 acts as a proapoptotic factor.…”

Section: Introductionmentioning

confidence: 99%

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TNF-α's effects on proliferation and apoptosis in human mesenchymal stem cells depend on RUNX2 expression

Ghali

Chauveau

Hardouin

et al. 2010

Journal of Bone and Mineral Research

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RUNX2 is a bone-specific transcription factor that plays a critical role in prenatal bone formation and postnatal bone development. It regulates the expression of genes that are important in committing cells into the osteoblast lineage. There is increasing evidence that RUNX2 is involved in osteoblast proliferation. RUNX2 expression increases during osteoblast differentiation, and recent data even suggest that it acts as a proapoptotic factor. The cytokine tumor necrosis factor a (TNF-a) is known to modulate osteoblast functions in a manner that depends on the differentiation stage. TNF-a affects the rate at which mesenchymal precursor cells differentiate into osteoblasts and induces apoptosis in mature osteoblasts. Thus we sought to establish whether or not the effects of TNF-a and fetal calf serum on proliferation and apoptosis in human mesenchymal stem cells (hMSCs) were dependent on RUNX2 level and activity. We transfected hMSCs with small interfering RNAs (siRNAs) directed against RUNX2 and found that they proliferated more quickly than control hMSCs transfected with a nonspecific siRNA. This increase in proliferation was accompanied by a rise in cyclin A1, B1, and E1 expression and a decrease in levels of the cyclin inhibitor p21. Moreover, we observed that RUNX2 silencing protected hMSCs from TNF-a's antiproliferative and apoptotic effects. This protection was accompanied by the inhibition of caspase-3 activity and Bax expression. Our results confirmed that RUNX2 is a critical link between cell fate, proliferation, and growth control. This study also suggested that, depending on the osteoblasts' differentiation stage, RUNX2 may control cell growth by regulating the expression of elements involved in hormone and cytokine sensitivity. ß

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Section: Discussionsupporting

confidence: 77%

Section: Discussionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

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TNF-α's effects on proliferation and apoptosis in human mesenchymal stem cells depend on RUNX2 expression

Ghali

Chauveau

Hardouin

et al. 2010

Journal of Bone and Mineral Research

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“…(26,27,33) In order to determine the functions of HDAC4 and HDAC5 in the Runx2-mediated suppression of Notch1 signaling, we performed a transcription reporter assay using HDAC4 and HDAC5. The transcriptional activity of Notch1-IC was repressed in Runx2-expressing cells, and the Runx2-induced suppression of Notch1 transcriptional activity was restored via the coexpression of HDAC4 and HDAC5 (Fig.…”

Section: Runx2 Inhibits Notch1 Transcriptional Activitymentioning

confidence: 99%

“…(25,(28)(29)(30) Recently, multiple biologic functions of Runx2 have been demonstrated in various cell types, including chondrocytes, endothelial cells, osteosarcoma cells, T-cell lymphomas, and breast cancer cells. (31)(32)(33)(34)(35) One of the central players in the osteoblast differentiation process is the Runx2 transcription factor, which coordinates multiple signals involved in osteoblast differentiation. Up to the present, several regulators such as Stat1, Twist, Hey1, and Notch1 have been shown to form inhibitory complexes with Runx2 and to inhibit osteoblast differentiation.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Notch1 signaling by Runx2 during osteoblast differentiation

Ann

Kim

Choi

et al. 2010

Journal of Bone and Mineral Research

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Notch1 genes encode receptors for a signaling pathway that regulates cell growth and differentiation in various contexts, but the role of Notch1 signaling in osteogenesis is not well defined. Notch1 controls osteoblast differentiation by affecting Runx2, but the question arises whether normal osteoblastic differentiation can occur regardless of the presence of Notch1. In this study, we observed the downregulation of Notch1 signaling during osteoblastic differentiation. BMPR‐IB/Alk6‐induced Runx2 proteins reduced Notch1 activity to a marked degree. Accumulated Runx2 suppressed Notch1 transcriptional activity by dissociating the Notch1‐IC‐RBP‐Jk complex. Using deletion mutants, we also determined that the N‐terminal domain of Runx2 was crucial to the binding and inhibition of the N‐terminus of the Notch1 intracellular domain. Notably, upregulation of the Runx2 protein level paralleled reduced expression of Hes1, which is a downstream target of Notch1, during osteoblast differentiation. Collectively, our data suggest that Runx2 is an inhibitor of the Notch1 signaling pathway during normal osteoblast differentiation. © 2011 American Society for Bone and Mineral Research.

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Proteasome inhibition with bortezomib suppresses growth and induces apoptosis in osteosarcoma

Shapovalov

Benavidez

Zuch

et al. 2010

Intl Journal of Cancer

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Osteosarcomas are primary bone tumors of osteoblastic origin that mostly affect adolescent patients. These tumors are highly aggressive and metastatic. Previous reports indicate that gain of function of a key osteoblastic differentiation factor, Runx2, leads to growth inhibition in osteosarcoma. We have previously established that Runx2 transcriptionally regulates expression of a major proapoptotic factor, Bax. Runx2 is regulated via proteasomal degradation, and proteasome inhibition has a stimulatory effect on Runx2. In this study, we hypothesized that proteasome inhibition will induce Runx2 and Runx2-dependent Bax expression sensitizing osteosarcoma cells to apoptosis. Our data showed that a proteasome inhibitor, bortezomib, increased Runx2 and Bax in osteosarcoma cells. In vitro, bortezomib suppressed growth and induced apoptosis in osteosarcoma cells but not in nonmalignant osteoblasts. Experiments involving intratibial tumor xenografts in nude mice demonstrated significant tumor regression in bortezomib-treated animals. Immunohistochemical studies revealed that bortezomib inhibited cell proliferation and induced apoptosis in osteosarcoma xenografts. These effects correlated with increased immunoreactivity for Runx2 and Bax. In summary, our results indicate that bortezomib suppresses growth and induces apoptosis in osteosarcoma in vitro and in vivo suggesting that proteasome inhibition may be effective as an adjuvant to current treatment regimens for these tumors. Published 2009 UICC.

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Runx2-mediated activation of the Bax gene increases osteosarcoma cell sensitivity to apoptosis

Cited by 61 publications

References 40 publications

TNF-α's effects on proliferation and apoptosis in human mesenchymal stem cells depend on RUNX2 expression

TNF-α's effects on proliferation and apoptosis in human mesenchymal stem cells depend on RUNX2 expression

Inhibition of Notch1 signaling by Runx2 during osteoblast differentiation

Proteasome inhibition with bortezomib suppresses growth and induces apoptosis in osteosarcoma

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