Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P43146 (tumour suppressor)
 5,935 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

BRCA1 is a tumour suppressor gene implicated in the predisposition to early onset breast and ovarian cancer. We have generated cell lines with inducible expression of BRCA1 to evaluate its role in mediating the cellular response to various chemotherapeutic drugs commonly used in the treatment of breast and ovarian cancer. Induction of BRCA1 in the presence of Taxol and Vincristine resulted in a dramatic increase in cell death; an effect that was preceded by an acute arrest at the G2/M phase of the cell cycle and which correlated with BRCA1 mediated induction of GADD45. A proportion of the arrested cells were blocked in mitosis suggesting activation of both a G2 and a mitotic spindle checkpoint. In contrast, no specific interaction was observed between BRCA1 induction and treatment of cells with a range of DNA damaging agents including Cisplatin and Adriamycin. Inducible expression of GADD45 in the presence of Taxol induced both G2 and mitotic arrest in these cells consistent with a role for GADD45 in contributing to these effects. Our results support a role for both BRCA1 and GADD45 in selectively regulating a G2/M checkpoint in response to antimicrotubule agents and raise the possibility that their expression levels in cells may contribute to the toxicity observed with these compounds.
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PMID:BRCA1 and GADD45 mediated G2/M cell cycle arrest in response to antimicrotubule agents. 1159 20

In vivo investigations on oncogenes and onco-suppressor genes may provide new findings on the potential carcinogenic effects of various cytostatic protocols inducing secondary tumours of the head and neck. Further surgeries are often necessary due to regional recurrence after the Cisplatin-supplemented BVM (Bleomycin, Vincristine, Methotrexate) protocol in the treatment of human head and neck tumours. Our earlier studies have illustrated the carcinogenic and mutagenic potential of Cisplatin. The effect of Cisplatin on the alteration of different onco- and suppressor genes has also been proven. Our present study aimed at investigating the early effects of the BVM and the CFu (Cisplatin, 5-Fluorouracil) protocols on early oncogene and tumour suppressor gene expressions in mice. Body weight equivalent amounts of cytostatics were administered intraperitoneally to 6- to 8-week-old, inbred, female CBA/Ca mice. Twenty-four, 48 and 72 hours after the treatment, RNA was isolated from the target organs and the quantitative expression of c-myc, Ha-ras and p53 genes were examined. The protocols caused detectable changes. A "short-term" in vivo test, the 24-hour examination of gene expression, is suitable for detecting early effects of carcinogen exposure. The alterations of gene expression, caused by the Cisplatin-containing protocol, draw attention to the probable role of Cisplatin in the development of regional recurrence and to the possibility of prevention.
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PMID:Early effects of different cytostatic protocols for head and neck cancer on oncogene activation in animal experiments. 1498 32

Cisplatin is an extremely effective chemotherapeutic agent used for the treatment of testicular and other solid tumours. It induces a variety of structural modifications in DNA, the most abundant being the GpG- and ApG-1,2-intrastrand cross links formed between adjacent purine bases. These cross links account for approximately 90% of cisplatin-induced DNA damage and are thought to be responsible for the cytotoxic activity of the drug. In human cells, the nucleotide excision repair (NER) process removes the intrastrand cross links from the genome, the efficiency of which is likely to be an important determinant of cisplatin cytotoxicity. We have investigated whether the p53 tumour suppressor status affects global NER of cisplatin-induced intrastrand cross links in human cells. We have used a (32)P-postlabelling method to monitor the removal of GpG- and ApG-intrastrand cross links from two human cell models (the 041TR system, in which p53 is regulated by a tetracycline-inducible promoter, together with WI38 fibroblasts and the SV40-transformed derivative VA13) that each differ in p53 status. We demonstrate that the absence of functional p53 leads to persistence of both cisplatin-induced intrastrand cross links in the genome, suggesting that p53 regulates NER of these DNA lesions. This observation extends the role of p53 in NER beyond enhancing the removal of environmentally induced DNA lesions to include those of clinical origin. Given the frequency of p53 mutations in human tumours, these results may have implications for the use of cisplatin in cancer chemotherapy.
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PMID:p53-dependent global nucleotide excision repair of cisplatin-induced intrastrand cross links in human cells. 1826 49

The epithelial-mesenchymal transition (EMT) induced by EGF promotes cervical cancer progression; however, the mechanisms underlying the EGF-induced EMT remain unclear. In this study, we reported that miR155 overexpression suppressed EGF-induced EMT, decreased migration/invasion capacities, inhibited cell proliferation and increased the chemo-sensitivity to DDP in human Caski cervical cancer cells. Further, the overexpression of miR155 increased TP53 expression but reduced SMAD2, and CCND1 expression levels. These data suggest that miR155 negatively regulates EGF-induced EMT. We conclude that miR155 does not act as an oncogene but as a tumour suppressor in Caski cells.
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PMID:Up-regulated miR155 reverses the epithelial-mesenchymal transition induced by EGF and increases chemo-sensitivity to cisplatin in human Caski cervical cancer cells. 2328 82

Periocular malignancies represent between 5% and 10% of all types of skin cancers. The incidence of eyelid (but also the periocular located) malignancies seems to differ in distribution across the continents. The incidence of eyelid tumours (but also the periocular located tumours) in a predominantly white population determined that BCC is the most common malignant periocular eyelid tumour in whites. This finding has been replicated consistently throughout the literature, with BCC representing 85-95% of all eyelid malignancies, SCC representing 3.4 - 12.6%, Seb Ca representing 0.6 - 10.2%, and both melanoma and Merkel cell carcinoma representing less than 1%. Most periocular skin cancers are associated with ultraviolet radiation (UVR) exposure. Ultraviolet radiation causes local immune suppression, which, coupled with DNA abnormalities in tumour suppressor genes and oncogenes, leads to the development of skin cancers. We are presenting a 62 - year - old patient with a small nodule about 2 cm away from the lower lid of his left eye. A tumour was surgically treated. Several years later there was a tumour relapse, treated with radiotherapy and subsequent chemotherapy with Endoxan and Cisplatin. After the second relapse, he was treated surgically in general anaesthesia by orbital exenteration, removal of the orbital floor and resection of zygomatic bone and the maxillary sinus. A couple of months later, he developed a tumour relapse in the scars and the area of a primary tumour with tumour progression. A possible therapy with Cetuximab or radiation therapy was discussed as a possible treatment option.
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PMID:Peri - and Intraocular Mutilating Advanced Squamous Cell Carcinoma: "Monsters Inside Your Body"? 2948 9

Cervical cancer is the fourth most common cause of mortality in women worldwide. In this study we investigated the effect of a tumour suppressor microRNA miR-214 in modulating the cell death against chemotherapeutic drugs like Doxorubicin, Cisplatin and Paclitaxel. CRISPR-facilitated knockdown and plasmid-based overexpression of miR-214 was performed in cervical cancer cell lines HeLa, C33A and CaSki. It was observed that knocking out miR-214 resulted in reduced apoptosis and cell migration upon drug treatments; while overexpression of miR-214 resulted in marginal increase in apoptosis and cell migration when treated with drugs. However, miR-214 had very little effect on production of reactive oxygen species. Our results also indicate that Doxorubicin was least effective and Paclitaxel most effective in inducing cell death. A combination of miR-214 overexpression and Paclitaxel treatment was found to be most effective in inducing cell death in cervical cancer cells. Analysis of cell cycle phases followed by apoptotic markers also showed that miR-214 overexpression along with Paclitaxel treatment caused an increase in PARP and decline of PI-3 kinase/Akt levels. Therefore, miR-214 levels determine the fate of the cancer cell during chemotherapeutic treatment.
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PMID:CRISPR-mediated knockdown of miR-214 modulates cell fate in response to anti-cancer drugs in HPV-negative and HPVpositive cervical cancer cells. 3255 5

Cisplatin resistance is a major challenge in cervical cancer (CC) chemotherapy. Growth arrest-specific 5 (GAS5) has been reported to be a tumour suppressor gene in CC. However, the mechanism of GAS5 in chemoresistance remains undetermined. Our research evaluated GAS5 expression in normal and CC tissues by qPCR and in situ hybridization (ISH). Statistical analysis was conducted to analyse the association of GAS5 expression with survival. Biochemical methods were used to screen upstream and downstream regulators of GAS5. Then, interactions were confirmed by ChIP, RNA pull-down, RNA immunoprecipitation (RIP), dual-luciferase reporter and real-time PCR assays. The cisplatin sensitivity of GAS5-overexpressing CC cells was demonstrated in vitro and in vivo. The results showed that low GAS5 expression was correlated with poor overall survival. Mechanistically, GAS5 was transcriptionally modulated by P-STAT3 and served as a competing endogenous RNA (ceRNA) of miR-21 to indirectly affect cisplatin sensitivity through PDCD4 regulation in CC cells. Animal studies confirmed that GAS5 enhanced cisplatin sensitivity and promoted PDCD4 expression in vivo. GAS5 was regulated by P-STAT3 and affected the sensitivity of CC to cisplatin-based chemotherapy through the miR-21/PDCD4 axis. This result may provide new insight into cisplatin-based therapy.
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PMID:Low GAS5 expression may predict poor survival and cisplatin resistance in cervical cancer. 3266 Dec 36