Targeting the E3 ubiquitin casitas B-lineage lymphoma decreases osteosarcoma cell growth and survival and reduces tumorigenesis

Sévère, Nicolas; Dieudonné, François-Xavier; Marty, Caroline; Modrowski, Dominique; Patiño-García, Ana; Lecanda, Fernando; Fromigué, Olivia; Marie, Pierre J.

doi:10.1002/jbmr.1667

Cited by 20 publications

(12 citation statements)

References 43 publications

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“…135 Consistently, we recently showed that c-Cbl protein expression is decreased in face of increased EGFR and PDGFR- α expression in human osteosarcoma tumors compared with normal bone. 136 This finding has therapeutic implications as ectopic c-Cbl expression in osteosarcoma cells could reduce the expression of EGFR and PDGFR- α , resulting in decreased cell proliferation and survival, and reduced incidence of lung metastasis in mice. 136 Thus, promoting RTK ubiquitination and degradation by targeting c-Cbl may prove to be efficient at reducing tumor growth and metastasis in cancers in which RTK expression is excessive (Figure 4).…”

Section: Cbl-mediated Ubiquitination: a Potential Target For Therapeumentioning

confidence: 96%

“…136 This finding has therapeutic implications as ectopic c-Cbl expression in osteosarcoma cells could reduce the expression of EGFR and PDGFR- α , resulting in decreased cell proliferation and survival, and reduced incidence of lung metastasis in mice. 136 Thus, promoting RTK ubiquitination and degradation by targeting c-Cbl may prove to be efficient at reducing tumor growth and metastasis in cancers in which RTK expression is excessive (Figure 4). This strategy may also be applied to Ewing sarcoma that is associated with increased IGF receptor activity.…”

Section: Cbl-mediated Ubiquitination: a Potential Target For Therapeumentioning

confidence: 96%

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E3 ubiquitin ligase-mediated regulation of bone formation and tumorigenesis

Sévère

2013

Cell Death Dis

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The ubiquitination–proteasome and degradation system is an essential process that regulates protein homeostasis. This system is involved in the regulation of cell proliferation, differentiation and survival, and dysregulations in this system lead to pathologies including cancers. The ubiquitination system is an enzymatic cascade that mediates the marking of target proteins by an ubiquitin label and thereby directs their degradation through the proteasome pathway. The ubiquitination of proteins occurs through a three-step process involving ubiquitin activation by the E1 enzyme, allowing for the transfer to a ubiquitin-conjugated enzyme E2 and to the targeted protein via ubiquitin-protein ligases (E3), the most abundant group of enzymes involved in ubiquitination. Significant advances have been made in our understanding of the role of E3 ubiquitin ligases in the control of bone turnover and tumorigenesis. These ligases are implicated in the regulation of bone cells through the degradation of receptor tyrosine kinases, signaling molecules and transcription factors. Initial studies showed that the E3 ubiquitin ligase c-Cbl, a multi-domain scaffold protein, regulates bone resorption by interacting with several molecules in osteoclasts. Further studies showed that c-Cbl controls the ubiquitination of signaling molecules in osteoblasts and in turn regulates osteoblast proliferation, differentiation and survival. Recent data indicate that c-Cbl expression is decreased in primary bone tumors, resulting in excessive receptor tyrosine kinase signaling. Consistently, c-Cbl ectopic expression reduces bone tumorigenesis by promoting tyrosine kinase receptor degradation. Here, we review the mechanisms of action of E3 ubiquitin ligases in the regulation of normal and pathologic bone formation, and we discuss how targeting the interactions of c-Cbl with some substrates may be a potential therapeutic strategy to promote osteogenesis and to reduce tumorigenesis.

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Section: Cbl-mediated Ubiquitination: a Potential Target For Therapeumentioning

confidence: 96%

Section: Cbl-mediated Ubiquitination: a Potential Target For Therapeumentioning

confidence: 96%

E3 ubiquitin ligase-mediated regulation of bone formation and tumorigenesis

Sévère

2013

Cell Death Dis

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“…2F, 2H). However, the effect of c-Cbl silencing on osteoblast markers was not always strictly related to c-Cbl levels, most probably because c-Cbl regulates the degradation of many proteins such as receptor tyrosine kinases [38,44] that may control osteoblast differentiation directly or indirectly.…”

Section: C-cbl Silencing Promotes Osteoblast Proliferation and Differmentioning

confidence: 99%

Promotion of Osteoblast Differentiation in Mesenchymal Cells Through Cbl-Mediated Control of STAT5 Activity

et al. 2013

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The identification of the molecular mechanisms controlling the degradation of regulatory proteins in mesenchymal stromal cells (MSC) may provide clues to promote MSC osteogenic differentiation and bone regeneration. Ubiquitin ligase-dependent degradation of proteins is an important process governing cell fate. In this study, we investigated the role of the E3 ubiquitin ligase c-Cbl in MSC osteoblast differentiation and identified the mechanisms involved in this effect. Using distinct shRNA targeting c-Cbl, we showed that c-Cbl silencing promotes osteoblast differentiation in murine and human MSC, as demonstrated by increased alkaline phosphatase activity, expression of phenotypic osteoblast marker genes (RUNX2, ALP, type 1 collagen), and matrix mineralization in vitro. Coimmunoprecipitation analyses showed that c-Cbl interacts with the transcription factor STAT5, and that STAT5 forms a complex with RUNX2, a master transcription factor controlling osteoblastogenesis. Silencing c-Cbl decreased c-Cblmediated STAT5 ubiquitination, increased STAT5 protein level and phosphorylation, and enhanced STAT5 and RUNX2 transcriptional activity. The expression of insulin like growth factor-1 (IGF-1), a target gene of STAT5, was increased by c-Cbl silencing in MSC and in bone marrow stromal cells isolated from c-Cbl deficient mice, suggesting that IGF-1 contributes to osteoblast differentiation induced by c-Cbl silencing in MSC. Consistent with these findings, pharmacological inhibition of STAT5 activity, or neutralization of IGF-1 activity, abrogated the positive effect of c-Cbl knockdown on MSC osteogenic differentiation. Taken together, the data provide a novel functional mechanism by which the ubiquitin ligase c-Cbl regulates the osteoblastic differentiation program in mesenchymal cells by controlling Cbl-mediated STAT5 degradation and activity.

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“…In vivo, la surexpression de c-Cbl dans un modèle murin d'ostéosar-come diminue la formation tumorale ainsi que le développement de métastases pulmonaires dans un modèle murin d'ostéosarcome. Nous avons montré que cet effet antitumoral de c-Cbl in vivo résulte d'une diminution de la prolifération cellulaire et d'une augmentation de l'apoptose des cellules tumorales, effets relayés par une diminution de l'expression des récepteurs PDGFR, EGFR et FGFR2 [33]. Ces données récentes montrent que le rôle antitumoral de c-Cbl passe par l'ubiquitination et la dégradation de ces récepteurs membranaires ( Figure 3B).…”

Section: Rôle Des Protéines Cbl Dans L'ostéogenèseunclassified