Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Loss of cell cycle control through the structural or functional aberration of checkpoint genes and their products is a potentially important process in carcinogenesis. In this study, a panel of well-characterised established human bladder cancer cell lines was screened by the polymerase chain reaction for homozygous loss of the cyclin-dependent kinase inhibitor genes p15, p16 and p27. The results demonstrate that, whereas there was no genetic loss of p27, homozygous deletion of both p15 and p16 genes occurred in seven of 13 (54%) independent bladder cell lines tested. Differential loss of either the p15 or p16 gene was not seen. The p15 and p16 genes are known to be juxtaposed on chromosome 9p21 at the locus of a putative tumour-suppressor gene involved in the initiation of bladder cancer. Cytogenetic analysis of the cell lines revealed karyotypes ranging from near diploid to near pentaploid with complex rearrangements of some chromosomes and a high prevalence of chromosome 9p rearrangements, although all cell lines contained at least one cytogenetically normal 9p21 region. These observations support a role for p15/p16 gene inactivation in bladder carcinogenesis and/or the promotion of cell growth in vitro and lend support to the hypothesis that homozygous deletion centred on 9p21 is a mechanism by which both p15 and p16 genes are co-inactivated.
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PMID:Loss of cyclin-dependent kinase inhibitor genes and chromosome 9 karyotypic abnormalities in human bladder cancer cell lines. 757 70

CIP1/WAF1, a critical downstream effector of tumor suppressor p53, encodes a cyclin-dependent kinase inhibitor. By Northern blot analysis, the CIP1/WAF1 mRNA level in the tumor was significantly lower than that in the corresponding normal liver from 19 Japanese patients with hepatocellular carcinoma (P < 0.05). In the tumor from only one out of 19 patients (5%), somatic mutations of the CIP1/WAF1 as well as that of p53 gene were identified by RT-PCR/SSCP analysis. These results suggest that the decreased CIP1/WAF1 expression is involved in the carcinogenesis or the progression of hepatocellular carcinoma.
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PMID:Decreased expression and rare somatic mutation of the CIP1/WAF1 gene in human hepatocellular carcinoma. 902 46

The cyclin-dependent kinase inhibitor p27Kip1 can inhibit the G1 to S transition of the cell cycle and is a putative tumor suppressor. However, our laboratory found that a variety of human cancer cell lines express relatively high levels of this protein and that this is often associated with increased expression of cyclin D1 or cyclin E. Therefore, in the present study we analyzed by immunohistochemistry the expression of p27Kip1 in a series of human tissue samples representing various stages of colon carcinogenesis, using 20 samples of normal colon mucosa, 20 hyperplastic polyps, 19 samples of adenomatous polyps, and 40 samples of various types of colorectal carcinomas. Parallel immunostaining was done for cyclin D1 and also for Ki67 to evaluate cell proliferation. An additional 17 human colon carcinoma samples, together with paired adjacent normal mucosa samples, were analyzed for levels of expression of the p27Kip1 protein by Western blot analysis, and 7 of these pairs of samples were examined by Northern blot analysis for levels of p27Kip1 mRNA. We did not find a positive or negative correlation between p27Kip1 expression and cell proliferation in the normal mucosa and tumor samples. There was, however, an inverse correlation between p27Kip1 and Ki67 expression in the lymphoid follicles present in the colonic mucosa. There was no evidence for a consistent increase or decrease in p27Kip1 expression in the mucosal cells during colon carcinogenesis, because the mean values for percentage p27Kip1-positive cells were similar in the normal mucosa, adenomatous polyps, and carcinoma samples. This is in contrast to Ki67 and cyclin D1 expression, which did show significant increases in mean values with tumor development. A subset (35%) of the carcinomas displayed diffuse cytoplasmic staining, in addition to nuclear staining, for p27Kip1, and in these cases the percentage of cells that were positive for p27Kip1 was higher than in cases that had only nuclear staining. There was a significant correlation between p27Kip1 expression and tumor grade; ie., well and moderately differentiated carcinomas had high p27Kip1 expression, whereas poorly differentiated carcinomas had lower expression. The Western blot analysis data on p27Kip1 expression confirmed this correlation. Comparisons of Northern and Western blots did not show a correlation between the level of p27Kip1 mRNA and the corresponding protein, a finding consistent with evidence that the p27Kip1 protein is regulated mainly via a posttranscriptional mechanism. The immunostaining studies revealed a significant correlation between high p27Kip1 protein expression and high cyclin D1 expression in the adenomatous polyps and in the subset of carcinomas that had only nuclear p27Kip1 expression. This may reflect the existence of a homeostatic feedback mechanism that is lost in the high-grade carcinomas that express low levels of p27Kip1.
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PMID:Localization and expression of p27KIP1 in multistage colorectal carcinogenesis. 942 67

Genetic predisposition plays an important role in the development of nearly 10% of cases of cutaneous malignant melanoma (CMM). The CDKN2A gene has been described as responsible for melanoma susceptibility in a proportion of families with CMM linked to 9p. CDKN2A encodes a cyclin-dependent kinase inhibitor also implicated in the carcinogenesis of several sporadic tumors. Even though the incidence of other cancers is higher in CMM families, pancreatic adenocarcinoma is the only other well demonstrated cancer associated with CDKN2A mutations in some CMM pedigrees. We describe a family with four cases of CMM, eight patients affected by other cancers, and nine patients affected by dysplastic nevus (DN) syndrome. A CDKN2A frameshift mutation (358delG) was present in all the CMM patients, in at least three of the patients with other cancers (CDKN2A status is unknown in four patients), and in only two of the DN patients (CDKN2A status is unknown in one patient). An absence of linkage between chromosome 9p markers and the 358delG CDKN2A mutation and DN was detected, indicating genetic heterogeneity for DN and CMM in this family. The study strongly suggests that CDKN2A mutations are involved not only in the predisposition to CMM but also to several other types of cancer.
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PMID:Inherited susceptibility to several cancers but absence of linkage between dysplastic nevus syndrome and CDKN2A in a melanoma family with a mutation in the CDKN2A (P16INK4A) gene. 943 68

The p16ink4/CDKN2/MTS1 tumor suppressor gene encodes a cyclin-dependent kinase inhibitor which plays an important role in regulation of the G1/S phase cell cycle checkpoint. Loss of heterozygosity (LOH) at the p16 locus, 9p21, has been documented in a wide variety of tumors including ovarian carcinoma. However, inactivating mutations of the remaining allele and homozygous deletions are relatively infrequent events in primary tumors, even in cases where expression of p16 at the mRNA and protein level is clearly absent. These findings initially cast doubt on the role of p16 as a tumor suppressor gene in vivo. Recently, an alternative mechanism of p16 inactivation involving methylation of the CpG island in the 5' region of the gene has been demonstrated in a number of malignancies and cell lines. In this study we have analyzed the methylation status of four CpG dinucleotides in a panel of 23 ovarian tumors using a multiplex PCR approach to correlate our findings with the LOH data in this region. Using the microsatellite markers D9S171 and D9S1679 LOH was demonstrated in 4/22 (18%) informative cases. All 23 tumors showed no evidence of methylation at the p16 locus including the 4 tumors demonstrating LOH at 9p21. These results suggest that methylation inactivation of the p16 gene does not play an important role in ovarian carcinogenesis.
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PMID:No evidence exists for methylation inactivation of the p16 tumor suppressor gene in ovarian carcinogenesis. 945 53

Because most non-melanocytic human skin cancers have p53 mutations, it is unclear whether the aberrant growth of these cancers is simply a result of the abrogation of a p53 downstream mediator, the universal cyclin-dependent kinase inhibitor p21WAF1. To investigate the role of p21WAF1 in human skin carcinogenesis, we studied its regulation in normal and p53-mutated immortalized human keratinocytes. In proliferating human normal keratinocytes (HNK), more wild-type p53 protein (wt p53) was expressed than in growth-arrested differentiating keratinocytes. However, the function of wt p53 as a transcriptional activator of the p21WAF1 gene was suppressed in proliferating keratinocytes. In response to ultraviolet B irradiation, expression of wt p53 increased in proliferating keratinocytes, but p21WAF1 transcriptional activation was not induced. Two isoforms of mdm2 (p57 and p90), which can bind to wt p53 and negatively regulate wt p53 function, were expressed in proliferating HNK, suggesting that mdm2 may play a role in the suppression of wt p53's function in proliferating HNK. Increased expression of p21WAF1 was detected in both Ca(2+)-induced growth-arrested and differentiating HNK, in which the wt p53 expression was down regulated. This reflects the complexity of the p53/p21WAF1 pathways of cell-cycle regulation and differentiation in keratinocytes. No p21WAF1 expression was detected in human immortalized keratinocytes (HaCaT) or in two ras-transformed variants, HaCaT ras I/7 and HaCaT ras II/3, which have two p53 mutations. Retrovirus-mediated expression of p21WAF1 stopped the growth of all these cell types, but expression of wt p53 did not affect the cells' growth properties. p21WAF1 also downregulated human telomerase RNA component mRNA expression in HaCaT cells. This novel function of p21WAF1 partly explains the suppression of telomerase activity by p21WAF1 expression in HaCaT. Taken together, these results are consistent with the idea that p21WAF1 successfully inhibits the growth of non-melanocytic skin cancers, even those with alterations in p53, p21ras, retinoblastoma gene product, and telomerase activity.
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PMID:Growth arrest of immortalized human keratinocytes and suppression of telomerase activity by p21WAF1 gene expression. 947 69

Since its discovery as a CDKI (cyclin-dependent kinase inhibitor) in 1993, the tumor suppressor p16 (INK4A/MTS-1/CDKN2A) has gained widespread importance in cancer. The frequent mutations and deletions of p16 in human cancer cell lines first suggested an important role for p16 in carcinogenesis. This genetic evidence for a causal role was significantly strengthened by the observation that p16 was frequently inactivated in familial melanoma kindreds. Since then, a high frequency of p16 gene alterations were observed in many primary tumors. In human neoplasms, p16 is silenced in at least three ways: homozygous deletion, methylation of the promoter, and point mutation. The first two mechanisms comprise the majority of inactivation events in most primary tumors. Additionally, the loss of p16 may be an early event in cancer progression, because deletion of at least one copy is quite high in some premalignant lesions. p16 is a major target in carcinogenesis, rivaled in frequency only by the p53 tumor-suppressor gene. Its mechanism of action as a CDKI has been elegantly elucidated and involves binding to and inactivating the cyclin D-cyclin-dependent kinase 4 (or 6) complex, and thus renders the retinoblastoma protein inactive. This effect blocks the transcription of important cell-cycle regulatory proteins and results in cell-cycle arrest. Although p16 may be involved in cell senescence, the physiologic role of p16 is still unclear. Future work will focus on studies of the upstream events that lead to p16 expression and its mechanism of regulation, and perhaps lead to better therapeutic strategies that can improve the clinical course of many lethal cancers.
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PMID:Role of the p16 tumor suppressor gene in cancer. 950 8

The p53 tumour suppressor gene is frequently mutated in oral squamous cell carcinomas. However, the downstream mechanism of p53 during oral carcinogenesis is not fully understood. The cyclin-dependent kinase inhibitor p21WAF1/CIP1 (p21), which can be induced by wild-type p53, functions as a downstream mediator of the antiproliferative and apoptosis-inducing actions of wild-type p53. To learn more about the roles of the p53 gene and its downstream mechanism, we evaluated p53 gene mutation and immunohistochemical expression of p53 and p21 in 20 cases of oral squamous cell carcinoma. p53 gene mutations were observed in 7 cases (35%). Overexpression of p53 was found in 4 of 13 cases with wild-type p53, and in 6 of 7 cases with p53 mutations. p21 expression was detected in 15 of 20 cases (75%). The expression of p21 correlated neither with mutated p53 mutation nor with p53 protein overexpression. p21 was expressed even in carcinomas in which molecular analysis revealed a nonsense mutation. In normal oral mucosa, p21 expression was limited in the differentiating spinous cell layer. However, dysplastic or hyperplastic epithelium adjacent to the tumour demonstrated the increased expression of p21 even in the proliferating basal cell layer. These molecular and immunohistochemical data did not show any correlation with various clinico-pathologic parameters. These results suggest that p53 gene mutations and altered expression of p21 are commonly involved in oral carcinogenesis, but do not correlate with each other or with the clinico-pathologic parameters. They also suggest that p21 expression in oral squamous cell carcinomas may be induced by a p53-independent pathway.
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PMID:Expression of p21WAF1/CIP1 is unrelated to p53 tumour suppressor gene status in oral squamous cell carcinomas. 969 54

p21WAF1/CIP1 protein is a cyclin-dependent kinase inhibitor, discovered to be a downstream effector of p53-dependent cell cycle regulation. In order to elucidate the significance of p21 expression in lung adenocarcinomas, we performed immunohistochemical analysis of p21, p53 and Ki-67 expression in surgically resected lung adenocarcinomas. In non-neoplastic tissue, a few bronchial and bronchiolar suprabasal and ciliated cells, and a few type II alveolar cells and alveolar macrophages in the peripheral lung, were p21 positive, but the positive rate in normal lung tissue was very low (<1%). All 91 lung adenocarcinomas examined showed p21 immunoreactivity: 39 cases (42.9%) and 52 cases (57.1%) showed high and low p21 expression levels, respectively. There was no significant correlation between p21 expression and p53 expression, the loss of heterozygosity status of the p53 gene, histological grade determined by the predominant histology, lymph node metastasis, pathological stage, tumor size, smoking history or gender. A positive, not inverse, correlation between p21 and Ki-67 expression was observed. We also observed heterogeneous expression of p21 in lung adenocarcinomas, i.e. in about two-thirds of the tumors, the tumor cells in the peripheral regions were p21 positive more frequently than were those in the central regions. More intense p21 expression tended to occur in the more highly differentiated areas. These results suggest that p21 is involved in tumor cell differentiation and the physiological mechanism that protects against tumor extension.
Carcinogenesis 1998 Oct
PMID:p21WAF1/CIP1 expression in primary lung adenocarcinomas: heterogeneous expression in tumor tissues and correlation with p53 expression and proliferative activities. 980 55

The polycyclic aromatic hydrocarbon (PAH) dibenzo[a,l]pyrene (DB[a,l]P), the most carcinogenic PAH tested in rodent bioassays, exerts its pathobiological activity via metabolic formation of electrophilically reactive DNA-binding fjord region (+)-syn-(11S,12R,13S,14R)- or (-)-anti-(11R,12S,13S,14R)-DB[a,l]P-dihydrodiol epoxides (DB[a,l]-PDEs). DB[a,l]P is metabolized to these DB[a,l]PDEs which bind to DNA in human mammary carcinoma MCF-7 cells. The molecular response of MCF-7 cells to DNA damage caused by DB[a,l]PDEs was investigated by analyzing effects on the expression of the tumor suppressor protein p53 and one of its target gene products, the cyclin-dependent kinase inhibitor p21WAF1. Treatment of MCF-7 cells with (+)-syn- and (-)-anti-DB[a,l]PDE at a concentration range of 0.001-0.1 microM resulted in DB[a,l]PDE-DNA adduct levels between 2 and 30, and 3 and 80 pmol/mg DNA, respectively, 8 h after exposure. (-)-anti-DB[a,l]PDE exhibited a higher binding efficiency that correlated with a significantly stronger p53 response at low concentrations of the dihydrodiol epoxides. The level of p53 increased by 6-8 h after treatment. The p21WAF1 protein amount exceeded control levels by 12 h and remained elevated for 96 h. At a dose of 0.01 microM (+)-syn-DB[a,l]PDE, an increase in p21WAF1 was observed in the absence of a detectable change in p53 levels. The results indicate that the increase in p53 induced by DB[a,l]PDEs in MCF-7 cells requires an adduct level of approximately 15 pmot/mg DNA and suggest that the level of adducts rather than the specific structure of the DB[a,l]PDE-DNA adduct formed triggers the p53 response. The PAH-DNA adduct level formed may determine whether p53 and p21VAF1 pathways respond, resulting in cell-cycle arrest, or fail to respond and increase the risk of mutation induction by these DNA lesions.
Carcinogenesis 1999 May
PMID:The level of DNA modification by (+)-syn-(11S,12R,13S,14R)- and (-)-anti-(11R,12S,13S,14R)-dihydrodiol epoxides of dibenzo[a,l]pyrene determined the effect on the proteins p53 and p21WAF1 in the human mammary carcinoma cell line MCF-7. 1033 4


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