WRAP53 promotes cancer cell survival and is a potential target for cancer therapy

Mahmoudi, Salah; Henriksson, Sofia; Farnebo, Lovisa; Roberg, Karin; Farnebo, Marianne

doi:10.1038/cddis.2010.90

Cited by 57 publications

(73 citation statements)

References 29 publications

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“…So here we used TCAB1 to represent the WRAP53 isoforms except α. Previously reported data in vitro suggested that overexpression of WRAP53 could induce cellular transformation while WRAP53 knockdown by exogenous siRNA on the other hand, could induce cellular apoptosis [16], also indicating potential oncogenic characteristics of TCAB1. Head and neck carcinoma is approximately the sixth most common cancer among global cancers [17,18], and the five year survival rate has remained at about 50% in the past decades [19].…”

Section: Introductionmentioning

confidence: 99%

TCAB1: a potential target for diagnosis and therapy of head and neck carcinomas

et al. 2014

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BackgroundWRAP53, including α, β and γ isoforms, plays an important role not only in the stability of p53 mRNA, but also in the assembly and trafficking of the telomerase holoenzyme. It has been considered an oncogene and is thought to promote the survival of cancer cells. The aim of this study was to detect the role of TCAB1 (except WRAP53α) in the occurrence and development of head and neck carcinomas.MethodsImmunohistochemistry was used to detect the TCAB1 expression in clinical specimen sections and performed western blotting to check the TCAB1 expression levels in cell lines. TCAB1 was depleted using shRNA lentivirus and the knockdown efficiency was assessed using q-PCR and Western blotting. We performed CCK-8 assays and flow cytometry to check the cell proliferation potential and used the trans-well assay to test the invasion ability in vitro. Xenografts were used to detect the tumor formation potential in vivo. Moreover, we performed cDNA microarray to investigate the candidate factors involved in this process.ResultsWe observed a notable overexpression of TCAB1 in head and neck carcinoma clinical specimens as well as in carcinoma cell lines. Knockdown of TCAB1 decreased the cellular proliferation potential and invasion ability in vitro. cDNA microarray analysis suggested the possible involvement of several pathways and factors associated with tumorigenesis and carcinoma development in the TCAB1-mediated regulation of cancers. Furthermore, the xenograft assay confirmed that the depletion of TCAB1 would inhibit tumor formation in nude mice. The immunohistochemistry results of the mice tumor tissue sections revealed that the cells in shTCAB1 xenografts showed decreased proliferation potential and increased apoptotic trend, meanwhile, the angiogenesis was inhibited in the smaller tumors form shTCAB1 cells.ConclusionsOur study demonstrated that depletion of TCAB1 decreased cellular proliferation and invasion potential both in vitro and in vivo. The data indicated that TCAB1 might facilitate the occurrence and development of head and neck carcinomas. In future, TCAB1 might be useful as a prognostic biomarker or a potential target for the diagnosis and therapy of head and neck carcinomas.

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Section: Introductionmentioning

confidence: 99%

TCAB1: a potential target for diagnosis and therapy of head and neck carcinomas

et al. 2014

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“…For example, inherited mutations in WRAP53b that affect its WD40 domain cause dyskeratosis congenita, a disorder involving bone marrow failure, premature aging, and cancer predisposition (Zhong et al 2011). Moreover, SNPs in WRAP53 or altered expression of the protein itself are associated with elevated risk for a variety of sporadic tumors and radioresistant head and neck cancer cells, hematoxicity, and disturbed DNA repair in workers exposed to benzene (Garcia-Closas et al 2007;Lan et al 2009;Schildkraut et al 2009;Mahmoudi et al 2011;Medrek et al 2013;Garvin et al 2014). Furthermore, patients with spinal muscular atrophy, a neurodegenerative disorder that is the leading genetic cause of infant mortality worldwide, exhibit loss of WRAP53b function (Mahmoudi et al 2010).…”

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confidence: 99%

The scaffold protein WRAP53β orchestrates the ubiquitin response critical for DNA double-strand break repair

et al. 2014

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The WD40 domain-containing protein WRAP53b (WD40 encoding RNA antisense to p53; also referred to as WDR79/TCAB1) controls trafficking of splicing factors and the telomerase enzyme to Cajal bodies, and its functional loss has been linked to carcinogenesis, premature aging, and neurodegeneration. Here, we identify WRAP53b as an essential regulator of DNA double-strand break (DSB) repair. WRAP53b rapidly localizes to DSBs in an ATM-, H2AX-, and MDC1-dependent manner. We show that WRAP53b targets the E3 ligase RNF8 to DNA lesions by facilitating the interaction between RNF8 and its upstream partner, MDC1, in response to DNA damage. Simultaneous binding of MDC1 and RNF8 to the highly conserved WD40 scaffold domain of WRAP53b facilitates their interaction and accumulation of RNF8 at DSBs. In this manner, WRAP53b controls proper ubiquitylation at DNA damage sites and the downstream assembly of 53BP1, BRCA1, and RAD51. Furthermore, we reveal that knockdown of WRAP53b impairs DSB repair by both homologous recombination (HR) and nonhomologous end-joining (NHEJ), causes accumulation of spontaneous DNA breaks, and delays recovery from radiation-induced cell cycle arrest. Our findings establish WRAP53b as a novel regulator of DSB repair by providing a scaffold for DNA repair factors.

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“…Previous studies have provided evidence indicating that WRAP53 is a potential oncoprotein whose overexpression can induce cell transformation and promote cancer cell survival, and whose knockdown leads to massive cancer cell death (Mahmoudi et al, 2011). Mędrek et al (2013) found WRAP53 to be associated with ovarian cancer risk in a Polish population, although only in relation to its rs2287497 and rs2287498 polymorphisms.…”

Section: Discussionmentioning

confidence: 99%

Association between the WRAP53 gene rs2287499 C>G polymorphism and cancer risk: A meta-analysis

et al. 2016

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ABSTRACT. The TP53 5'-untranslated region flanking the gene WRAP53 (also known as WDR79 and TCAB1) has been hypothesized to be associated with cancer risk due to its critical function in regulating p53 levels. In this review, we analyzed the association between the WRAP53 gene rs2287499 C>G polymorphism and risk of cancer using five case-control studies, comprising seven datasets. All analyses were performed using RevMan software. In the overall analysis, no significant association between rs2287499 and risk of cancer was found. We then conducted subgroup tests, stratifying the data by cancer type, ethnicity, sample source, and quality score. Only the brain and breast cancer subgroups returned significant results, but with conflicting implications. Our concerns regarding this are discussed in detail. In conclusion, the rs2287499 polymorphism may be associated with risk of cancer. Further studies taking into consideration a broader range of cancer types and different ethnicities are warranted.

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WRAP53 promotes cancer cell survival and is a potential target for cancer therapy

Cited by 57 publications

References 29 publications

TCAB1: a potential target for diagnosis and therapy of head and neck carcinomas

TCAB1: a potential target for diagnosis and therapy of head and neck carcinomas

The scaffold protein WRAP53β orchestrates the ubiquitin response critical for DNA double-strand break repair

Association between the WRAP53 gene rs2287499 C>G polymorphism and cancer risk: A meta-analysis

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