Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have previously shown that fetal rat brain cells, preneuronal (PC12), and hepatocyte (CWSV-1) cells undergo apoptosis during choline deficiency (CD). The PC12 and epithelial cell culture models were used to determine the molecular mechanism by which CD induces apoptosis. Our data indicate that CD leads to both growth arrest and apoptosis in a subpopulation of cells, which correlate with the up-regulation of the tumor suppressor protein p53 and concurrent up-regulation of the cyclin-dependent kinase-inhibitor p21(WAF1/CIP1). Additionally, CD induced both a G1/S and a G2/M arrest. Transient transfection of a dominant negative p53 (p53DN) construct into PC12 cells, which inhibited endogenous p53 activation, significantly reduced the induction of apoptosis associated with CD. Interestingly, CD also induced the persistent activation of the transcription factor NF-kappaB. Activation of NF-kappaB has been shown to promote cell survival and proposed to antagonize p53. Consistent with this, expression of a super-repressor form of IkappaBalpha (SR-IkappaBalpha) that functions to strongly inhibit NF-kappaB activation, profoundly enhanced cell death during CD. In summary, these results suggest that the effects of CD on apoptosis and subsequent cell survival are mediated through two different signaling pathways, p53 and NF-kappaB, respectively. Taken together, our data demonstrates the induction of opposing mechanisms associated with nutrient deficiency that may provide a molecular mechanism by which CD promotes carcinogenesis.
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PMID:Opposing regulation of choline deficiency-induced apoptosis by p53 and nuclear factor kappaB. 1148 91

CDC25A, CDC25B and CDC25C belong to a family of protein phosphatases which activate the cyclin-dependent kinase at different points of the cell cycle. According to accumulating evidence, CDC25A and CDC25B seem to possess oncogenic properties. We have analysed these expressions by immunohistochemistry, western blot and RT-PCR in a series of 100 patients with squamous cell carcinoma of the oesophagus. When compared with non-cancerous cells, CDC25A and CDC25B were strongly expressed in the cytoplasm of cancer cells, with positive (+) classification in 46% (46 cases) and 48% (48 cases), respectively. There was no significant correlation between CDC25A and CDC25B expression, nor was there any association with the expression of other cell cycle-regulating molecules, including cyclin D1, Rb, p16(INK4), p27(KIP1)and PCNA (proliferating cell nuclear antigen). CDC25A (+), as well as CDC25B (+), was more frequently found in patients with deeper tumour invasion and lymph node metastasis, while tumour size was correlated only with CDC25A expression. Postoperative survival was significantly poorer for CDC25A (+) patients than CDC25A (-) patients, but was not affected by the CDC25B status. Nuclear localization of CDC25A was observed in 51 cases (51%), regardless of its cytoplasmic expression, and was not associated with clinico-pathological factors or prognosis. Multivariate analysis revealed only the CDC25A status to be an independent significant prognostic factor among these biological and clinico-pathological factors. CDC25A but not CDC25B may be a new prognostic factor for squamous cell carcinoma of the oesophagus. Thus, regulation of the G1 checkpoint in the cell cycle may be important in oesophageal carcinogenesis, which may also involve many other oncogenes.
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PMID:Clinical significance of CDC25A and CDC25B expression in squamous cell carcinomas of the oesophagus. 1148 74

Inactivation or down-regulation of the cell-cycle inhibitors p16MTS1, p21WAF1, and p27KIP1 is involved in the carcinogenesis of various human tumors. In cervical squamous cell carcinomas that are associated with human papillomavirus (HPV) infection, the expression or function of these proteins is impaired by the action of viral oncoproteins E6 and E7. Comparably less is known about the role of these cyclin-dependent kinase inhibitors in cervical adenocarcinomas, 15-40% of which are HPV negative. Therefore, we studied the expression of p16MTS1, p21WAF1, and p27KIP1 by immunohistochemistry in 60 cervical adenocarcinomas. HPV infection was determined by PCR, and HPV 16 and 18 E6/E7 oncogene expression was analyzed by RNA-RNA in situ hybridization. We found significant correlations of strong p16 expression with HPV 16/18 infection and HPV 16/18 E6/E7 oncogene expression (P=0.001). Moderate or strong p16 expression was also observed in 41% of HPV-negative carcinomas, indicating that HPV-independent mechanisms might also lead to p16 overexpression. In addition, stronger p21 and p27 expression was significantly associated with the detection of HPV 16 or 18 E6/E7 transcripts (P=0.015 and 0.030, respectively). Obviously, the tumor suppressor action of these proteins can be overcome in HPV-positive lesions. In contrast, absent or low p16, p21, and p27 immunostaining was observed in most HPV-negative cervical adenocarcinomas and might contribute to carcinogenesis in these tumors.
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PMID:Expression of cyclin-dependent kinase inhibitors p16MTS1, p21WAF1, and p27KIP1 in HPV-positive and HPV-negative cervical adenocarcinomas. 1149 40

P21 (WAF1), P53 and cyclin D1 belong to the cell cycle-regulating family of proteins, and the loss of activity of proteins P53 and P21 (WAF1) seems to be one of the most important regulatory mechanisms of carcinogenesis in colorectal cancer. The purpose of this study was to assess the relationship between P21 (WAF1), P53 and cyclin D1 immunoreactivity, and to evaluate the prognostic significance of their expression. Tissue sections from 122 paraffin-embedded colorectal carcinomas were immunostained with monoclonal antibodies. Positivity for P21 (WAF1) was found in 48 cases (39%), positivity for P53 in 96 cases (70%) and positivity for cyclin D1 in all the cases (100%). Statistical analyses revealed a statistically significant inverse correlation between P53 and P21 (WAF1)-immunopositivity and between P21 (WAF1)-immunopositivity and the degree of cyclin D1-immunopositivity, as well as an inverse correlation between P21 (WAF1) expression and clinical stage. In univariate analysis, down-regulation of P21 (WAFI) expression was associated with poor prognosis, but multivariate analysis did not confirm its independent prognostic significance. In Cox's analysis only regional lymph node invasion and hepatic metastases were proven as independent prognostic parameters. Our investigation results suggest that in colorectal cancer, the induction of P21 (WAF1) may occur mostly in a P53-dependent pathway. P21 (WAF1), as the main cyclin-dependent kinase (CDK)-inhibitor, may also inhibit the activity of cyclins such as cyclin D1.
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PMID:P21 (WAF1) expression in colorectal cancer: correlation with P53 and cyclin D1 expression, clinicopathological parameters and prognosis. 1170 Aug 90

Methylseleninic acid (MSA) is a monomethylated form of selenium effective in inhibiting cell growth in vitro and experimental mammary carcinogenesis in vivo. MSA offers particular advantage in cell culture experiments because it is stable in solution and provides a monomethylated form of selenium that can be reduced by cellular reducing systems and released nonenzymatically within a cell. In the present study, MSA was used to elucidate the mechanisms of cell growth inhibition by selenium. These studies were performed using a mouse mammary hyperplastic epithelial cell line, TM6. MSA induced a rapid arrest of synchronized cells in the G(1) phase of the cell cycle. This effect was accompanied by a reduction in total cellular levels of cyclin D1. Whereas MSA had no effect on total levels of the cyclin-dependent kinase (CDK)4, the amount of CDK4 immunoprecipitated with cyclin D1 in MSA-treated cells was decreased as was the kinase activity of the immunoprecipitated complex. MSA did not significantly affect cyclin E or associated regulatory molecules. Treatment with MSA suppressed the hyperphosphorylated form of retinoblastoma (Rb) with a commensurate increase in the hypophosphorylated form. Levels of E2F-1 bound to Rb also were elevated. Levels of insulin-like growth factor-I receptor and phosphorylated Akt were reduced by MSA. It is concluded that MSA induces a G(1) arrest in the cell cycle. This effect may be induced by MSA via its modulation of insulin-like growth factor-I-mediated signal transduction leading to inhibition of Akt activation and limitation of cyclin D1-CDK4-mediated phosphorylation of Rb.
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PMID:Mechanisms of cell cycle arrest by methylseleninic acid. 1178 73

p21WAF1,CIP1,SDI 1 is a specific inhibitor of cyclin-dependent kinase and a tumor suppressor involved in the pathogenesis of a variety of malignancies. Cdk1/p34cdc2 plays a crucial role during mitosis. The immunoreactivity of p21 WAF1,CIP1,SDI 1 and cdk1/p34cdc2 was evaluated in adenomas and adenocarcinomas of the human large bowel. The expression of p21WAF1,CW1,SDI 1 was detected in 5 out of 15 adenomas (33.3 %) and in 13 out of 36 adenocarcinomas (36 %). Cdk1/p34cdc2 was expressed in 11 out of 15 adenomas (73.3%) and in 18 out of 36 adenocarcinomas (50%). In conclusion, our results indicate that there is an expression of cdk1/p34cdc2 in colorectal adenomas and absence of p21 WAF1,CIP1,SDI 1 in both colorectal adenomas and carcinomas. These results suggest that the proliferative activity of colonic cancer might not be solely dependent on control of the cell cycle by p21 WAF1,CIP1,SDI Cdk1/p34cdc2 expression, in a high percentage of both adenomas and adenocarcinomas suggest that this phenomenon may be an early event in colorectal carcinogenesis.
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PMID:Cdk1/P34Cdc2 and P21waf expression in colorectal adenomas and carcinomas. 1187 50

p21(Waf1/Cip1/Sdi1) is best known as a broad-specificity inhibitor of cyclin/cyclin-dependent kinase complexes, but p21 also interacts with many other regulators of transcription or signal transduction. p21 induction, which is mediated by p53 and by p53-independent mechanisms, is essential for the onset of cell cycle arrest in damage response and cell senescence. The effects of p21 knockout in mice and its expression patterns in human cancer are consistent with a role for p21 as both a tumour suppressor and an oncogene. Several functions of p21 are likely to promote carcinogenesis and tumour progression. These include endoreduplication and abnormal mitosis that develop in tumour cells after release from p21-induced growth arrest, the ability of p21 to inhibit apoptosis through several different mechanisms, and its ability to stimulate transcription of secreted factors with mitogenic and anti-apoptotic activities. The latter effects of p21 show close resemblance to paracrine activities of senescent cells and to tumour-promoting functions of stromal fibroblasts. Therapeutic strategies targeting the oncogenic consequences of p21 expression may provide a new approach to chemoprevention and treatment of cancer.
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PMID:Oncogenic functions of tumour suppressor p21(Waf1/Cip1/Sdi1): association with cell senescence and tumour-promoting activities of stromal fibroblasts. 1188 Jan 76

The dysregulation of the molecular events governing cell cycle control is emerging as a central theme of oral carcinogenesis. Regulatory pathways responding to extracellular signaling or intracellular stress and DNA damage converge on the cell cycle apparatus. Abrogation of mitogenic and anti-mitogenic response regulatory proteins, such as the retinoblastoma tumor suppressor protein (pRB), cyclin D1, cyclin-dependent kinase (CDK) 6, and CDK inhibitors (p21(WAF1/CIP1), p27(KIP1), and p16(INK4a)), occur frequently in human oral cancers. Cellular responses to metabolic stress or genomic damage through p53 and related pathways that block cell cycle progression are also altered during oral carcinogenesis. In addition, new pathways and cell cycle regulatory proteins, such as p12(DOC-1), are being discovered. The multistep process of oral carcinogenesis likely involves functional alteration of cell cycle regulatory members combined with escape from cellular senescence and apoptotic signaling pathways. Detailing the molecular alterations and understanding the functional consequences of the dysregulation of the cell cycle apparatus in the malignant oral keratinocyte will uncover novel diagnostic and therapeutic approaches.
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PMID:Cell cycle dysregulation in oral cancer. 1209 37

The INK4 locus has two promoters and encodes two unique proteins that share exons in different reading frames, p16(INK4a) and p14(ARF). The p16(INK4a) protein, by inhibiting cyclin-dependent kinase, down regulates Rb-E2F and leads to cell cycle arrest in the G1 phase. The p14(ARF) protein interacts with the MDM2 protein, neutralizing MDM2-mediated degradation of p53. Since p53/Rb genes are not altered in malignant mesothelioma, additional components of these pathways, such as p16(INK4a) and p14(ARF), are candidates for inactivation. In this study, we have examined p16(INK4a) and p14(ARF) alterations (gene deletion, mutation and promoter methylation) in 45 primary malignant mesothelioma specimens. Fourteen patients (31%) had altered p16; four tumors had a methylated promoter region (8.8%), 10 tumors showed p16 to be deleted (22.2%), and one tumor had a point mutation (2%). We did not find any instances of methylation in the p14(ARF) 5'-CpG island. Patients whose tumors had p16 deletion were significantly younger than those with methylation, and, in the patients whose lungs were studied for the prevalence of asbestos fibers, those with any p16 alteration had lower fiber counts than those with no p16 alteration. Hence, p16 gene alteration is relatively common in malignant mesothelioma, while p14(ARF) is rarely, if ever, methylated. Our data suggest that deletion of p16 occurs in a relatively susceptible subset of the population.
Carcinogenesis 2002 Jul
PMID:Alterations of the p16(INK4) locus in human malignant mesothelial tumors. 1211 69

3,3'-Diindolylmethane (DIM) is a promising cancer chemopreventive agent derived from Brassica food plants. To determine whether this natural indole has a direct growth inhibitory effect on human breast cancer cells, we examined the cell cycle regulatory effects of DIM in estrogen-dependent (MCF-7) and estrogen-independent (MDA-MB-231) human breast cancer cell lines. Results of flow cytometry studies showed that DIM treatment produced a marked increase (from 51 to 79%) in the proportion of cells in the G(1) phase of the cell cycle, regardless of estrogen-receptor status. Analyses of G(1)-acting cell cycle components indicated that the enzymatic activity of cyclin-dependent kinase (CDK) 2 was also strongly reduced. Western blot analyses showed that, concurrent with the DIM-induced cell cycle arrest, DIM stimulated a rapid and pronounced increase in levels of the CDK inhibitor, p21(WAF1/CIP1) (p21). Northern blot analysis demonstrated that DIM increased p21 mRNA expression with a maximal 6-7-fold induction, and exposure to cycloheximide did not block the response. Similar increases in expression of p21 protein and mRNA were observed in both MCF-7 and MDA-MB-231 human breast cancer cells, suggesting that DIM induction of p21 expression is independent of estrogen-receptor signaling and p53. Transient transfection of 5'-deletion constructs of the p21 promoter demonstrated that the first 291 bp segment of the proximal promoter, which contains six promoter specific transcription factor 1 (Sp1) elements, maintained DIM responsiveness. Consistent with a role for Sp1 in this response, a reporter construct driven by three consensus Sp1 binding sites was responsive to DIM. In addition, electrophoretic mobility shift assays showed that DIM induced the binding of Sp1 and Sp3 to the consensus Sp1 responsive element. Thus, our observations have uncovered an antiproliferative pathway for DIM that implicates Sp1/Sp3-induced expression of p21 as a target for cell cycle control in human breast cancer cells.
Carcinogenesis 2002 Aug
PMID:3,3'-Diindolylmethane (DIM) induces a G(1) cell cycle arrest in human breast cancer cells that is accompanied by Sp1-mediated activation of p21(WAF1/CIP1) expression. 1215 47


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