p53 and Retinoblastoma protein (pRb): A complex network of interactions

Godefroy, Nelly; Lemaire, Christophe; Mignotte, Bernard; Vayssière, Jean-Luc

doi:10.1007/s10495-006-5543-y

Cited by 19 publications

(8 citation statements)

References 35 publications

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“…We observed a dose-dependent increase in mutant-p53 expression in OVCAR-3 cells, which is consistent with our previous report that cells respond to FBA-TPQ damage regardless of their p53 status [6]. We also observed down-regulation of MDM2 and a concomitant decrease in E2F1, and increased expression of Rb, p21 and p27 [30], [31], indicating that the activation of the p53-MDM2 feedback loop is likely responsible for the FBA-TPQ treatment-induced increase in the apoptosis and cell cycle arrest and the decrease in cell growth and proliferation in A2780 and OVCAR-3 cells. The Akt signaling pathway plays critical roles in regulating cell survival [32], [33].…”

Section: Discussionsupporting

confidence: 92%

Experimental Therapy of Ovarian Cancer with Synthetic Makaluvamine Analog: In Vitro and In Vivo Anticancer Activity and Molecular Mechanisms of Action

Chen

Guo

et al. 2011

PLoS ONE

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The present study was designed to determine the biological effects of novel marine alkaloid analog 7-(4-fluorobenzylamino)-1,3,4,8-tetrahydropyrrolo[4,3,2-de]quinolin-8(1H)-one (FBA-TPQ) on human ovarian cancer cells for its anti-tumor potential and the underlying mechanisms as a novel chemotherapeutic agent. Human ovarian cancer cells (A2780 and OVCAR-3), and Immortalized non-tumorigenic human Ovarian Surface Epithelial cells (IOSE-144), were exposed to FBA-TPQ for initial cytotoxicity evaluation (via MTS assay kit, Promega). The detailed in-vitro (cell level) and in-vivo (animal model) studies on the antitumor effects and possible underlying mechanisms of action of the compounds were then performed. FBA-TPQ exerted potent cytotoxicity against human ovarian cancer A2780 and OVCAR-3 cells as an effective inhibitor of cell growth and proliferation, while exerting lesser effects on non-tumorigenic IOSE-144 cells. Further study in the more sensitive OVCAR-3 cell line showed that it could potently induce cell apoptosis (Annexin V-FITC assay), G2/M cell cycle arrest (PI staining analysis) and also dose-dependently inhibit OVCAR-3 xenograft tumors' growth on female athymic nude mice (BALB/c, nu/nu). Mechanistic studies (both in vitro and in vivo) revealed that FBA-TPQ might exert its activity through Reactive Oxygen Species (ROS)-associated activation of the death receptor, p53-MDM2, and PI3K-Akt pathways in OVCAR-3 cells, which is in accordance with in vitro microarray (Human genome microarrays, Agilent) data analysis (GEO accession number: GSE25317). In conclusion, FBA-TPQ exhibits significant anticancer activity against ovarian cancer cells, with minimal toxicity to non-tumorigenic human IOSE-144 cells, indicating that it may be a potential therapeutic agent for ovarian cancer.

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Section: Discussionsupporting

confidence: 92%

Experimental Therapy of Ovarian Cancer with Synthetic Makaluvamine Analog: In Vitro and In Vivo Anticancer Activity and Molecular Mechanisms of Action

Chen

Guo

et al. 2011

PLoS ONE

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“… 29 E6/E7 oncoproteins can inactivate two tumour suppressor proteins p53 and pRB and thereby promote atypical cell growth. 30 The expression level of E6/E7 oncoproteins might differentiate the types of HPV infection; with HPV types with low E6/E7 expression being transient with low-risk of cancer induction. 16 In contrast, HPV types with a high level or long-standing expression of E6/E7 oncoproteins are probably associated with a higher risk of inducing cancer.…”

Section: Discussionmentioning

confidence: 99%

Feasibility study of a human papillomavirus E6 and E7 oncoprotein test for the diagnosis of cervical precancer and cancer

Zhang¹,

Cao²,

Zheng³

et al. 2018

J Int Med Res

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ObjectiveTo evaluate the clinical value of human papillomavirus (HPV) E6 and E7 oncoprotein (HPV E6/E7) detection in the early screening of cervical cancer.MethodsThis prospective study evaluated all patients with suspected cervical intraepithelial neoplasia (CIN) as identified by the presence of at least one positive indicator from a ThinPrep cytologic test (TCT) and/or a Hybrid Capture 2 (HC2) HPV DNA test. The levels of E6/E7 oncoproteins were determined using Western blot analysis. The diagnostic value of the HPV E6/E7 protein assay was compared with the clinical diagnosis from TCT, HC2 and the gold standard of cervical biopsy histology.ResultsA total of 450 patients were enrolled in the study and based on histological findings, 102 patients were diagnosed with CIN1 (22.7%), 241 with CIN2 (53.6%), 96 with CIN3 (21.3%) and 11 with squamous cell carcinoma (2.4%). For a diagnosis of CIN2+, although the sensitivity of the HPV E6/E7 assay was lower than HC2 (65.5% versus 96.6%, respectively), the specificity was higher (38.2% versus 5.9%, respectively). The sensitivity of the HPV E6/E7 assay was higher than TCT (65.5% versus 36.2%, respectively).ConclusionMeasuring HPV E6/E7 oncoprotein levels is a potential new biomarker for HPV type 16.

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“…Potential additional roles, including pro-apoptotic functions of pRb have been suggested [26]. While most studies have indicated an anti-apoptotic role of pRb [34], some studies have shown pRb to enhance apoptosis following γ-irradation [25] as well as doxorubicin-induced DNA damage [19] which is more in accordance with its role as a tumor suppressor. Here we found the apoptotic response to doxorubicin treatment to be restored by transfecting the RB1 -deficient C-33 A and Saos-2 cell lines with wild-type pRb, but only to a minor degree when transfecting the pRb point mutants, supporting a pro-apoptotic function of pRb in response to anthracycline therapy (Figure 6a and 6b).…”

Section: Discussionmentioning

confidence: 99%

Identification and characterization of retinoblastoma gene mutations disturbing apoptosis in human breast cancers

et al. 2010

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BackgroundThe tumor suppressor pRb plays a key role regulating cell cycle arrest, and disturbances in the RB1 gene have been reported in different cancer forms. However, the literature reports contradictory findings with respect to a pro - versus anti - apoptotic role of pRb, and the consequence of alterations in RB1 to chemotherapy sensitivity remains unclear. This study is part of a project investigating alterations in pivotal genes as predictive factors to chemotherapy sensitivity in breast cancer.ResultsAnalyzing 73 locally advanced (stage III) breast cancers, we identified two somatic and one germline single nucleotide changes, each leading to amino acid substitution in the pRb protein (Leu607Ile, Arg698Trp, and Arg621Cys, respectively). This is the first study reporting point mutations affecting RB1 in breast cancer tissue. In addition, MLPA analysis revealed two large multiexon deletions (exons 13 to 27 and exons 21 to 23) with the exons 21-23 deletion occurring in the tumor also harboring the Leu607Ile mutation. Interestingly, Leu607Ile and Arg621Cys point mutations both localize to the spacer region of the pRb protein, a region previously shown to harbor somatic and germline mutations. Multiple sequence alignment across species indicates the spacer to be evolutionary conserved. All three RB1 point mutations encoded nuclear proteins with impaired ability to induce apoptosis compared to wild-type pRb in vitro. Notably, three out of four tumors harboring RB1 mutations displayed primary resistance to treatment with either 5-FU/mitomycin or doxorubicin while only 14 out of 64 tumors without mutations were resistant (p = 0.046).ConclusionsAlthough rare, our findings suggest RB1 mutations to be of pathological importance potentially affecting sensitivity to mitomycin/anthracycline treatment in breast cancer.

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p53 and Retinoblastoma protein (pRb): A complex network of interactions

Cited by 19 publications

References 35 publications

Experimental Therapy of Ovarian Cancer with Synthetic Makaluvamine Analog: In Vitro and In Vivo Anticancer Activity and Molecular Mechanisms of Action

Experimental Therapy of Ovarian Cancer with Synthetic Makaluvamine Analog: In Vitro and In Vivo Anticancer Activity and Molecular Mechanisms of Action

Feasibility study of a human papillomavirus E6 and E7 oncoprotein test for the diagnosis of cervical precancer and cancer

Identification and characterization of retinoblastoma gene mutations disturbing apoptosis in human breast cancers

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