PAX3-FKHR Transformation Increases 26 S Proteasome-dependent Degradation of p27Kip1, a Potential Role for Elevated Skp2 Expression

Zhang, Lei; Wang, Chiayeng

doi:10.1074/jbc.m205424200

Cited by 45 publications

(20 citation statements)

References 60 publications

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“…The latter (p21 and p27) are observed to have lower expression in aRMS than eRMS, an effect that can be reversed by the putative HDAC inhibitor butyrate [40]. Further downstream in the G 1 /S checkpoint, p27 degradation is increased in a Pax3:Foxo1a-dependent manner, attributed to the Pax3:Foxo1a target gene product, Skp2 [11,41]. Interestingly, in other tumors p27 loss desensitizes Rb1 null tumor cells to Arf-mediated apoptosis.…”

Section: Discussionmentioning

confidence: 99%

Rb1 loss modifies but does not initiate alveolar rhabdomyosarcoma

Kikuchi

Taniguchi²,

Chen³

et al. 2013

Skeletal Muscle

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BackgroundAlveolar rhabdomyosarcoma (aRMS) is a myogenic childhood sarcoma frequently associated with a translocation-mediated fusion gene, Pax3:Foxo1a.MethodsWe investigated the complementary role of Rb1 loss in aRMS tumor initiation and progression using conditional mouse models.ResultsRb1 loss was not a necessary and sufficient mutational event for rhabdomyosarcomagenesis, nor a strong cooperative initiating mutation. Instead, Rb1 loss was a modifier of progression and increased anaplasia and pleomorphism. Whereas Pax3:Foxo1a expression was unaltered, biomarkers of aRMS versus embryonal rhabdomyosarcoma were both increased, questioning whether these diagnostic markers are reliable in the context of Rb1 loss. Genome-wide gene expression in Pax3:Foxo1a,Rb1 tumors more closely approximated aRMS than embryonal rhabdomyosarcoma. Intrinsic loss of pRb function in aRMS was evidenced by insensitivity to a Cdk4/6 inhibitor regardless of whether Rb1 was intact or null. This loss of function could be attributed to low baseline Rb1, pRb and phospho-pRb expression in aRMS tumors for which the Rb1 locus was intact. Pax3:Foxo1a RNA interference did not increase pRb or improve Cdk inhibitor sensitivity. Human aRMS shared the feature of low and/or heterogeneous tumor cell pRb expression.ConclusionsRb1 loss from an already low pRb baseline is a significant disease modifier, raising the possibility that some cases of pleomorphic rhabdomyosarcoma may in fact be Pax3:Foxo1a-expressing aRMS with Rb1 or pRb loss of function.

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Section: Discussionmentioning

confidence: 99%

Rb1 loss modifies but does not initiate alveolar rhabdomyosarcoma

Kikuchi

Taniguchi²,

Chen³

et al. 2013

Skeletal Muscle

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“…Recent findings suggest that the two models are not mutually exclusive and both may contribute to tumorigenesis. Indeed, ectopic expression of the Pax3-FOXO1 fusion protein results in an elevated level of Skp2 (Zhang and Wang, 2003). Moreover, ARMS cell lines that bear the t(2;13) chromosomal translocation exhibit higher levels of Skp2 when compared to normal skeletal muscle cells (Zhang and Wang, 2003).…”

Section: Foxo In Cancermentioning

confidence: 99%

“…Indeed, ectopic expression of the Pax3-FOXO1 fusion protein results in an elevated level of Skp2 (Zhang and Wang, 2003). Moreover, ARMS cell lines that bear the t(2;13) chromosomal translocation exhibit higher levels of Skp2 when compared to normal skeletal muscle cells (Zhang and Wang, 2003). Based on the observation that FOXO1 is degraded via ubiquitin-dependent proteasome pathway through interacting with Skp2 (Huang et al, 2005) and that FOXO protein degradation often accompanies cell transformation (Hu et al, 2004;Huang et al, 2005), it is tempting to speculate that oncogenic Pax3-FOXO1 fusion protein not only transactivates expression of tumor-promoter genes, but also leads to a complete loss of the function of FOXOs via ubiquitin-mediated proteasomal degradation.…”

Section: Foxo In Cancermentioning

confidence: 99%

FOXOs, cancer and regulation of apoptosis

2008

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Forkhead box O (FOXO) transcription factors are involved in multiple signaling pathways and play critical roles in a number of physiological and pathological processes including cancer. The importance of FOXO factors ascribes them under multiple levels of regulation including phosphorylation, acetylation/deacetylation, ubiquitination and protein-protein interactions. As FOXO factors play a pivotal role in cell fate decision, mounting evidence suggests that FOXO factors function as tumor suppressors in a variety of cancers. FOXOs are actively involved in promoting apoptosis in a mitochondriaindependent and -dependent manner by inducing the expression of death receptor ligands, including Fas ligand and tumor necrosis factor-related apoptosis-inducing ligand, and Bcl-2 family members, such as Bim, bNIP3 and Bcl-X L , respectively. An understanding of FOXO proteins and their biology will provide new opportunities for developing more effective therapeutic approaches to treat cancer.

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“…Notable changes include elevated expression of positive cell-cycle regulators such as cyclin D types (Zhang et al, 2004), cdk4 (Ragazzini et al, 2004), and Skp2 (Zhang and Wang, 2007), as well as repression of negative cell-cycle regulators such as cyclin inhibitors p16 Ink4a (Iolascon et al, 1996;Obana et al, 2003), p21 (Moretti et al, 2002), p27 (Zhang and Wang, 2003), and p57 (Roeb et al, 2007). Ink4A and cdk4 mutations occur more frequently in ARMS.…”

Section: Growth Defectsmentioning

confidence: 99%

Childhood Rhabdomyosarcoma

Wang

2011

J Dent Res

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Rhabdomyosarcoma (RMS) is a morphologically and clinically heterogeneous group of malignant tumors that resemble developing skeletal muscle and is the most common soft-tissue sarcoma in children and adolescents. The most prominent sites involve head and neck structures (~40%), genito-urinary track (~25%), and extremities (~20%). Embryonal (ERMS) and alveolar (ARMS) are the two major RMS subtypes that are distinct in their morphology and genetic make-up. The prognosis for this cancer depends strongly on tumor size, location, staging, and child's age. In general, ERMS has a more favorable outcome, whereas the mortality rate remains high in patients with ARMS, because of its aggressive and metastatic nature. Over the past two decades, researchers have made concerted efforts to delineate genetic and epigenetic changes associated with RMS pathogenesis. These molecular signatures have presented golden opportunities to design targeted therapies for treating this aggressive cancer. This article highlights recent advances in understanding the molecular pathogenesis of RMS, and addresses promising research areas for further exploration.

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PAX3-FKHR Transformation Increases 26 S Proteasome-dependent Degradation of p27Kip1, a Potential Role for Elevated Skp2 Expression

Cited by 45 publications

References 60 publications

Rb1 loss modifies but does not initiate alveolar rhabdomyosarcoma

Rb1 loss modifies but does not initiate alveolar rhabdomyosarcoma

FOXOs, cancer and regulation of apoptosis

Childhood Rhabdomyosarcoma

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