X-linked Inhibitor of Apoptosis Protein (XIAP) Regulates PTEN Ubiquitination, Content, and Compartmentalization

Themsche, Céline Van; Leblanc, Valérie; Parent, Stefan; Asselin, Éric

doi:10.1074/jbc.c109.009522

Cited by 141 publications

(116 citation statements)

References 25 publications

(26 reference statements)

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“…Previous studies have shown the regulatory mechanism for PTEN stability. PTEN can be ubiquitinated and degradaded by several ubiquitin E3 ligases, such as NEDD4 and the X-linked inhibitor of apoptosis protein Wang et al, 2007;Van Themsche et al, 2009). Phosphorylation of PTEN by casein kinase 2 or GSK3b also controls PTEN stability by promoting ubiquitination (Torres and Pulido, 2001;Al-Khouri et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

Loss of Mel-18 induces tumor angiogenesis through enhancing the activity and expression of HIF-1α mediated by the PTEN/PI3K/Akt pathway

et al. 2011

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Mel-18 has been implicated in several processes in tumor progression, in which the Akt pathway is involved as an important key molecular event. However, the function of Mel-18 in human cancers has not been fully established yet. Here, we examined the effect of Mel-18 on tumor angiogenesis in human breast cancer, and found that Mel-18 was a novel regulator of HIF-1a. Mel-18 negatively regulated the HIF-1a expression and its target gene VEGF transcription during both normoxia and hypoxia. We demonstrated that Mel-18 regulated the HIF-1a expression and activity via the PI3K/Akt pathway. Loss of Mel-18 downregulated Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) expression, consequently activating the PI3K/Akt/MDM2 pathway, and leading to an increase of HIF-1a protein level. Mel-18 modulated the HIF-1a transcriptional activity via regulating the cytoplasmic retention of FOXO3a, a downstream effector of Akt, and recruitment of HIF-1a/CBP complex to the VEGF promoter. Furthermore, our data shows that Mel-18 blocked tumor angiogenesis both in vitro and in vivo. Mel-18 overexpression inhibited in vitro tube formation in human umbilical endothelial cells (HUVECs). Xenografts in NOD/SCID mice derived from stably Mel-18 knocked down MCF7 human breast cancer cells showed increased tumor volume, microvessel density, and phospho-Akt and HIF-1a expression levels. In conclusion, our findings provide that Mel-18 is a novel regulator of tumor angiogenesis through regulating HIF-1a and its target VEGF expressions mediated by the PTEN/PI3K/Akt pathway, suggesting a new tumor-suppressive role of Mel-18 in human breast cancer.

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Section: Discussionmentioning

confidence: 99%

Loss of Mel-18 induces tumor angiogenesis through enhancing the activity and expression of HIF-1α mediated by the PTEN/PI3K/Akt pathway

et al. 2011

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“…In addition to direct inhibition of caspase activation in vivo, XIAP can modulate apoptosis through alternative mechanisms associated with its function as an E3 ubiquitin ligase (21,52). Further studies to delineate these mechanisms could provide additional insight into the pathobiology of fibrotic wound repair.…”

Section: Discussionmentioning

confidence: 99%

X-Linked Inhibitor of Apoptosis Regulates Lung Fibroblast Resistance to Fas-Mediated Apoptosis

Ajayi

Sisson

Higgins

et al. 2013

Am J Respir Cell Mol Biol

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The accumulation of apoptosis-resistant fibroblasts within fibroblastic foci is a characteristic feature of idiopathic pulmonary fibrosis (IPF), but the mechanisms underlying apoptosis resistance remain unclear. A role for the inhibitor of apoptosis (IAP) protein family member X-linked inhibitor of apoptosis (XIAP) has been suggested by prior studies showing that (1) XIAP is localized to fibroblastic foci in IPF tissue and (2) prostaglandin E 2 suppresses XIAP expression while increasing fibroblast susceptibility to apoptosis. Based on these observations, we hypothesized that XIAP would be regulated by the profibrotic mediators transforming growth factor (TGF)b-1 and endothelin (ET)-1 and that increased XIAP would contribute to apoptosis resistance in IPF fibroblasts. To address these hypotheses, we examined XIAP expression in normal and IPF fibroblasts at baseline and in normal fibroblasts after treatment with TGF-b1 or ET-1. The role of XIAP in the regulation of fibroblast susceptibility to Fas-mediated apoptosis was examined using functional XIAP antagonists and siRNA silencing. In concordance with prior reports, fibroblasts from IPF lung tissue had increased resistance to apoptosis compared with normal lung fibroblasts. Compared with normal fibroblasts, IPF fibroblasts had significantly but heterogeneously increased basal XIAP expression. Additionally, TGF-b1 and ET-1 induced XIAP protein expression in normal fibroblasts. Inhibition or silencing of XIAP enhanced the sensitivity of lung fibroblasts to Fasmediated apoptosis without causing apoptosis in the absence of Fas activation. Collectively, these findings support a mechanistic role for XIAP in the apoptosis-resistant phenotype of IPF fibroblasts.Keywords: myofibroblast; idiopathic pulmonary fibrosis; inhibitor of apoptosis; lung fibrosis; apoptosis Mesenchymal cells display a dynamic spectrum of phenotypes ranging between an undifferentiated state (fibroblast) and a differentiated state (myofibroblast) (1, 2). Although these effector cells are essential for the homeostatic reestablishment of normal architecture and function after tissue injury, the persistence of these cells is associated with fibrosis (3, 4). The resolution phase of normal wound repair coincides with the reduction of fibroblast numbers by apoptosis, but the triggers of apoptosis in normal wound repair and the mechanisms underlying the persistence of fibroblasts during fibrotic wound repair remain poorly understood (5, 6). The profibrotic mediators transforming growth factor (TGF)b-1 and endothelin (ET)-1 have been found to promote resistance to apoptotic stimuli in fibroblasts, and the antifibrotic lipid mediator prostaglandin (PG)E 2 has been shown to increase the responsiveness of these cells to apoptotic stimuli, supporting a role for dysregulation of fibroblast apoptosis in the pathogenesis of fibrosis (7-12).Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease of unknown etiology that is characterized by progressive alveolar fibrosis (13,14). The overall prognosis of patie...

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“…The NEDD4-1 and XIAP ubiquitin E3 ligases ubiquitinate PTEN. [50][51][52] PTEN phosphatase activity is also regulated by oxidization. At the center of PTEN's phosphatase catalytic site is a cysteine nucleophile, which is subject to oxidization.…”

Section: Pseudo-pten and Other Oncogenes Decoys For Mirnasmentioning

confidence: 99%

Targeting the translational apparatus to improve leukemia therapy: roles of the PI3K/PTEN/Akt/mTOR pathway

et al. 2011

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X-linked Inhibitor of Apoptosis Protein (XIAP) Regulates PTEN Ubiquitination, Content, and Compartmentalization

Cited by 141 publications

References 25 publications

Loss of Mel-18 induces tumor angiogenesis through enhancing the activity and expression of HIF-1α mediated by the PTEN/PI3K/Akt pathway

Loss of Mel-18 induces tumor angiogenesis through enhancing the activity and expression of HIF-1α mediated by the PTEN/PI3K/Akt pathway

X-Linked Inhibitor of Apoptosis Regulates Lung Fibroblast Resistance to Fas-Mediated Apoptosis

Targeting the translational apparatus to improve leukemia therapy: roles of the PI3K/PTEN/Akt/mTOR pathway

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