Grail as a molecular determinant for the functions of the tumor suppressor p53 in tumorigenesis

Chen, Y. C.; Chan, James; Chiu, Yi-Lin; Liu, S. T.; Lozano, Guillermina; Wang, S. L.; Ho, Ching‐Liang; Huang, Shih Ming

doi:10.1038/cdd.2013.1

Cited by 37 publications

(53 citation statements)

References 30 publications

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“…We propose that this integrin may be integrated in the growing list of molecular determinants of the p53 tumorsuppressor activity. [61][62][63] Response to chemotherapy may be hindered by p53-mediated cell cycle arrest or senescence. 64,65 As shown here, functional inhibition of the α5β1 integrin may represent a new way to sensitize glioma cells to the p53-dependent proapoptotic effect of Nutlin-3a.…”

Section: Discussionmentioning

confidence: 99%

Integrin α5β1 and p53 convergent pathways in the control of anti-apoptotic proteins PEA-15 and survivin in high-grade glioma

et al. 2015

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Integrin α5β1 expression is correlated with a worse prognosis in high-grade glioma. We previously unraveled a negative crosstalk between integrin α5β1 and p53 pathway, which was proposed to be part of the resistance of glioblastoma to chemotherapies. The restoration of p53 tumor-suppressor function is under intensive investigations for cancer therapy. However, p53-dependent apoptosis is not always achieved by p53-reactivating compounds such as Nutlin-3a, although full transcriptional activity of p53 could be obtained. Here we investigated whether integrin α5β1 functional inhibition or repression could sensitize glioma cells to Nutlin-3a-induced p53-dependent apoptosis. We discovered that α5β1 integrin-specific blocking antibodies or small RGD-like antagonists in association with Nutlin-3a triggered a caspase (Casp) 8/Casp 3-dependent strong apoptosis in glioma cells expressing a functional p53. We deciphered the molecular mechanisms involved and we showed the crucial role of two anti-apoptotic proteins, phosphoprotein enriched in astrocytes 15 (PEA-15) and survivin in glioma cell apoptotic outcome. PEA-15 is under α5β1 integrin/AKT (protein kinase B) control and survivin is a p53-repressed target. Moreover, interconnections between integrin and p53 pathways were revealed. Indeed PEA-15 repression by specific small-interfering RNA (siRNA)-activated p53 pathway to repress survivin and conversely survivin repression by specific siRNA decreased α5β1 integrin expression. This pro-apoptotic loop could be generalized to several glioma cell lines, whatever their p53 status, inasmuch PEA-15 and survivin protein levels were decreased. Our findings identify a novel mechanism whereby inhibition of α5β1 integrin and activation of p53 modulates two anti-apoptotic proteins crucially involved in the apoptotic answer of glioma cells. Importantly, our results suggest that high-grade glioma expressing high level of α5β1 integrin may benefit from associated therapies including integrin antagonists and repressors of survivin expression.

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Section: Discussionmentioning

confidence: 99%

Integrin α5β1 and p53 convergent pathways in the control of anti-apoptotic proteins PEA-15 and survivin in high-grade glioma

et al. 2015

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“…RNF128 (also known as Grail, a gene related to anergy in lymphocytes) is an E3 ubiquitin ligase functioning as a regulator of anergy and cytokine production 12-14. It was shown to play an important role in controlling Th2 development through a negative feedback loop 13-14.…”

Section: Introductionmentioning

confidence: 99%

“…It was shown to play an important role in controlling Th2 development through a negative feedback loop 13-14. A recent report found that RNF128 was a p53-interacting glycoprotein and may be crucial in p53-induced apoptosis under variable stress conditions 12. The transcription factor p53, a well-known tumor suppressor encoded by the TP53 gene, regulates genes critical for cell cycle arrest, senescence and apoptosis to maintain genome stability 15-17.…”

Section: Introductionmentioning

confidence: 99%

Downregulation of RNF128 Predicts Progression and Poor Prognosis in Patients with Urothelial Carcinoma of the Upper Tract and Urinary Bladder

Lee¹,

Wang²,

Huang³

et al. 2016

J. Cancer

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Background: The TP53 tumor suppressor gene plays a crucial role in the carcinogenesis of many malignancies, including urothelial carcinoma (UC). Overexpression of p53 is associated with poor prognosis in UC. Recently, RING finger protein 128 (RNF128) was shown to be involved in p53-induced apoptosis, forming a negative feedback loop. However, the significance of RNF128 in patients with UC remains unknown. In this study, our aim was to evaluate the expression of RNF128 in UC and to assess its predictive and prognostic value in a well-established cohort.Methods: Through data mining from a published transcriptome (GSE31684), RNF128 was identified as the most differentially expressed gene in UC among those associated with negative regulation of the cytokine biosynthetic process (GO:0042036). Its immunoexpression was further evaluated using the H-scores of 340 patients with upper urinary tract UC (UTUC) and 295 with urinary bladder UC (UBUC). The scores were correlated with clinicopathological features, disease-specific survival (DSS) and metastasis-free survival (MeFS). We also used Western blot analysis to evaluate RNF128 protein expression in human urothelial cell (HUC) lines.Results: Downregulation of RNF128 expression was significantly associated with advanced pT stage (p<0.001), high histological grade (UTUC, p<0.001; UBUC, p=0.035), nodal metastasis (UTUC, p<0.001; UBUC, p=0.001), vascular invasion (UTUC, p<0.001; UBUC, p=0.008) and high mitotic rate (UTUC, p=0.003; UBUC, p=0.023). Low expression of RNF128 was an adverse prognosticator for DSS (UTUC, p<0.0001; UBUC, p<0.0001) and MeFS (UTUC, p<0.0001; UBUC, p=0.0002). Moreover, low expression was predictive of poor DSS (UTUC, p=0.006; UBUC, p=0.003) and MeFS (UTUC, p=0.009; UBUC, p=0.036) in multivariate comparisons. Western blot analysis showed that the RNF128 protein was downregulated in invasive urothelial cancer cell lines.Conclusion: Our findings showed that downregulation of RNF128 was correlated with cancer invasiveness and metastasis as well as reduced survival in patients with UTUC and UBUC, identifying RNF128 as a prognostic factor in UC.

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“…p53 is a transcription factor that has been shown to play a major role in the cell's response to oncogenic stresses and tumour suppression by inducing cell cycle arrest, senescence, anti-oxidative stress responses or apoptosis (reviewed in [139])[140]. With ~50% of all human malignancies carrying a mutation in the p53 gene, the tumour suppressor is one of the most commonly mutated proteins in human cancers [141].…”

Section: Introductionmentioning

confidence: 99%

Screening for E3-Ubiquitin ligase inhibitors: challenges and opportunities

et al. 2014

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The ubiquitin proteasome system (UPS) plays a role in the regulation of most cellular pathways, and its deregulation has been implicated in a wide range of human pathologies that include cancer, neurodegenerative and immunological disorders and viral infections. Targeting the UPS by small molecular regulators thus provides an opportunity for the development of therapeutics for the treatment of several diseases. The proteasome inhibitor Bortezomib was approved for treatment of hematologic malignancies by the FDA in 2003, becoming the first drug targeting the ubiquitin proteasome system in the clinic. Development of drugs targeting specific components of the ubiquitin proteasome system, however, has lagged behind, mainly due to the complexity of the ubiquitination reaction and its outcomes. However, significant advances have been made in recent years in understanding the molecular nature of the ubiquitination system and the vast variety of cellular signals that it produces. Additionally, improvement of screening methods, both in vitro and in silico, have led to the discovery of a number of compounds targeting components of the ubiquitin proteasome system, and some of these have now entered clinical trials. Here, we discuss the current state of drug discovery targeting E3 ligases and the opportunities and challenges that it provides.

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Grail as a molecular determinant for the functions of the tumor suppressor p53 in tumorigenesis

Cited by 37 publications

References 30 publications

Integrin α5β1 and p53 convergent pathways in the control of anti-apoptotic proteins PEA-15 and survivin in high-grade glioma

Integrin α5β1 and p53 convergent pathways in the control of anti-apoptotic proteins PEA-15 and survivin in high-grade glioma

Downregulation of RNF128 Predicts Progression and Poor Prognosis in Patients with Urothelial Carcinoma of the Upper Tract and Urinary Bladder

Screening for E3-Ubiquitin ligase inhibitors: challenges and opportunities

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