Enhanced Proliferative Potential of Hematopoietic Cells Expressing Degradation-resistant c-Myb Mutants

Corradini, Francesca; Cesi, Vincenzo; Bartella, Viviana; Pani, Elisabetta; Bussolari, Rita; Candini, Olivia; Calabretta, Bruno

doi:10.1074/jbc.m504703200

Cited by 31 publications

(46 citation statements)

References 53 publications

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“…It has been reported that the c-Myb protein is phosphorylated at multiple sites and degraded by a ubiquitin-proteasome pathway (Bies et al, , 2001Kanei-Ishii et al, 2004a, b;Corradini et al, 2005). In this study, we investigated the mechanism of c-Myb degradation.…”

Section: Discussionmentioning

confidence: 99%

“…The pathway activated by Wnt-1 signaling has been reported to promote c-Myb ubiquitin proteasome-dependent degradation through NLKmediated phosphorylation at multiple sites (Kanei-Ishii et al, 2004a, b). It has also been reported that inhibition of the phosphatidylinositol 3-kinase/Akt/GSK3b pathway enhances the stability of c-Myb (Corradini et al, 2005). Moreover, there are several reports that have tried to identify the critical phosphorylation site(s) for ubiquitin proteasome-dependent degradation of c-Myb, although it is still unclear as to which aas are essential for both phosphorylation and degradation (Bies and Wolff, 1997;Bies et al, 1999Bies et al, , 2000Kanei-Ishii et al, 2004a, b;Corradini et al, 2005).…”

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Fbw7 promotes ubiquitin-dependent degradation of c-Myb: involvement of GSK3-mediated phosphorylation of Thr-572 in mouse c-Myb

et al. 2009

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Expression of oncoprotein c-Myb oscillates during hematopoiesis and hematological malignancies. Its quantity is not only regulated through transcriptional control but also through the ubiquitin-proteasome pathway, accompanied by phosphorylation, although the mechanisms are poorly understood. In this report, we tried to identify an E3 ubiquitin ligase, which targets c-Myb for ubiquitin-dependent degradation. We found that an F-box protein, Fbw7, interacted with c-Myb, which is mutated in numerous cancers. Fbw7 facilitated ubiquitylation and degradation of c-Myb in intact cells. Moreover, depletion of Fbw7 by RNA interference delayed turnover and increased the abundance of c-Myb in myeloid leukemia cells concomitantly, and suppressed the transcriptional level of g-globin, which receives transcriptional repression from c-Myb. In addition, we analysed sites required for both ubiquitylation and degradation of c-Myb. We found that Thr-572 is critical for Fbw7-mediated ubiquitylation in mouse c-Myb using sitedirected mutagenesis. Fbw7 recognized the phosphorylation of Thr-572, which was mediated by glycogen synthase kinase 3 (GSK3). In consequence, the c-Myb protein was markedly stabilized by the substitution of Thr-572 to Ala. These observations suggest that SCF Fbw7 ubiquitin ligase regulates phosphorylation-dependent degradation of c-Myb protein.

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Section: Discussionmentioning

confidence: 99%

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Fbw7 promotes ubiquitin-dependent degradation of c-Myb: involvement of GSK3-mediated phosphorylation of Thr-572 in mouse c-Myb

et al. 2009

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“…The murine IL-3 dependent 32Dcl3 myeloid precursor cell line was cultured and retrovirally transduced with MigRI empty vector, MigRI-c-Myb-HA or MigRI-Δ(358-452) c-Myb as previously described [7]. Cells were then subsequently transduced with pLXSP-Bcl-2 and subjected to puromycin-resistance selection.…”

Section: Cell Lines and Retroviral Transductionsmentioning

confidence: 99%

“…These cells were purified and transduced with the MigRI empty vector, the full-length c-Myb or the Δ(358-452) c-Myb to assess the biological consequences of expressing a c-Myb mutant with enhanced protein stability [7].…”

Section: Effects Of a Stable C-myb Mutant On Murine Hematopoietic Promentioning

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A degradation-resistant c-Myb mutant cooperates with Bcl-2 in enhancing proliferative potential and survival of hematopoietic cells

Corradini

Bussolari

Cerioli

et al. 2007

Blood Cells, Molecules, and Diseases

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The c-myb gene is preferentially expressed in primitive hematopoietic cell and plays a central role in the control of cell proliferation, differentiation and survival by regulating the transcription of several genes implicated in these processes including the antiapoptotic Bcl-2.We show here that, compared to wild-type c-Myb, overexpression of a degradation resistant cMyb mutant [Δ(358-452) c-Myb] enhances the clonogenic potential of hematopoietic progenitors as indicated by increased cytokine-dependent primary and secondary colony formation of Lin − Sca-1 + Kit + mouse marrow cells.Moreover, proliferation assays of IL-3 dependent myeloid precursor 32Dcl3 cells co-expressing Bcl-2 and c-Myb indicate that these cells continue to proliferate in the absence of IL-3 and this effect is more apparent in cells expressing the degradation resistant Δ(358-452) c-Myb. Interestingly, overexpression of Δ(358-452) c-Myb is by itself sufficient to protect 32Dcl3 cells from apoptosis induced by IL-3 deprivation; moreover, these cells are also increased in number which most likely reflects the enhanced proliferative potential conferred by Δ(358-452) c-Myb to apoptosis-resistant cells.

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Cadherin‐3 is a novel oncogenic biomarker with prognostic value in glioblastoma

et al. 2022

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Glioblastoma (GBM) is the most common and malignant primary brain tumor in adults. The prognosis of patients is very poor, with a median overall survival of ~ 15 months after diagnosis. Cadherin‐3 (also known as P‐cadherin), a cell–cell adhesion molecule encoded by the CDH3 gene, is deregulated in several cancer types, but its relevance in GBM is unknown. In this study, we investigated the functional roles, the associated molecular signatures, and the prognostic value of CDH3/P‐cadherin in this highly malignant brain tumor. CDH3/P‐cadherin mRNA and protein levels were evaluated in human glioma samples. Knockdown and overexpression models of P‐cadherin in GBM were used to evaluate its functional role in vitro and in vivo. CDH3‐associated gene signatures were identified by enrichment analyses and correlations. The impact of CDH3 in the survival of GBM patients was assessed in independent cohorts using both univariable and multivariable models. We found that P‐cadherin protein is expressed in a subset of gliomas, with an increased percentage of positive samples in grade IV tumors. Concordantly, CDH3 mRNA levels in glioma samples from The Cancer Genome Atlas (TCGA) database are increased in high‐grade gliomas. P‐cadherin displays oncogenic functions in multiple knockdown and overexpression GBM cell models by affecting cell viability, cell cycle, cell invasion, migration, and neurosphere formation capacity. Genes that were positively correlated with CDH3 are enriched for oncogenic pathways commonly activated in GBM. In vivo, GBM cells expressing high levels of P‐cadherin generate larger subcutaneous tumors and cause shorter survival of mice in an orthotopic intracranial model. Concomitantly, high CDH3 expression is predictive of shorter overall survival of GBM patients in independent cohorts. Together, our results show that CDH3/P‐cadherin expression is associated with aggressiveness features of GBM and poor patient prognosis, suggesting that it may be a novel therapeutic target for this deadly brain tumor.

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Enhanced Proliferative Potential of Hematopoietic Cells Expressing Degradation-resistant c-Myb Mutants

Cited by 31 publications

References 53 publications

Fbw7 promotes ubiquitin-dependent degradation of c-Myb: involvement of GSK3-mediated phosphorylation of Thr-572 in mouse c-Myb

Fbw7 promotes ubiquitin-dependent degradation of c-Myb: involvement of GSK3-mediated phosphorylation of Thr-572 in mouse c-Myb

A degradation-resistant c-Myb mutant cooperates with Bcl-2 in enhancing proliferative potential and survival of hematopoietic cells

Cadherin‐3 is a novel oncogenic biomarker with prognostic value in glioblastoma

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