Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.22 (cdc2)
 8,319 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

An understanding of the biological significance of the multiple genetic alterations identified in clinical bladder cancers to the stepwise pathogenesis of the disease is evolving. Alterations in p53 and pRb, products of the chromosomes 17p13 TP53 and 13q14 RB tumor suppressor genes, occur in approximately 50% and approximately 33% of bladder cancers respectively, and are associated with later stage, higher grade disease. p53 and pRb alterations are also known to occur in early stage bladder carcinoma in situ where they are thought to represent a poor prognosis for tumor progression. Allelic loss of genes on 9p21 occurs in approximately 50% of bladder cancers, but whether the only critical gene in this region is the CDKN2/p16 cyclin/CDK inhibitor is at present uncertain. Amplification and/or overexpression of the oncogenes epidermal growth factor receptor and erbB2 are associated with later stage disease. Finally, recent findings generated using in vitro transformation systems with human uroepithelial cells provide strong evidence that loss of genes on 3p, which occurs in approximately 20% of bladder cancers, and/or gain of genes on 20q play an important role in blocking HUC cellular senescence. This latter phenotype should represent a critical step in oncogenesis, as cells that do not senesce can survive to accumulate the multiple genetic alterations associated with invasive and metastatic bladder cancers. Further understanding of the biochemical mechanisms underlying these genetic changes will provide the additional information needed to design better strategies for bladder cancer intervention and treatment.
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PMID:A molecular genetic model of human bladder cancer pathogenesis. 889 68

Transfection and transgenic mouse experiments supported an oncogenic role for cyclin D1 in breast cancer. We recently reported that noninvasive carcinoma in situ lesions of the human breast overexpress cyclin D, suggesting that this molecular event may represent a valuable target for chemoprevention. The purpose of the present series of investigations was to identify agents which could reduce the cyclin D expression of breast cells. We report that 9-cis retinoic acid (9-cis RA) and all trans retinoic acid (tRA) inhibited the cyclin D1 and D3 expression levels of human MCF-7, ZR-75 and T-47D breast carcinoma cells in vitro. Where detectable, similar trends were observed in the immortalized, HBL-100 and MCF-10A breast cell lines. Cyclin D2 was undetectable. The effect of retinoids was both dose- and time-dependent, and correlated with altered cell cycle kinetics and proliferative status. Retinoids were also found to inhibit the expression levels of other cell cycle related proteins, including Cdk2 and Cdk4, resulting in lower kinase activities. In contrast to other breast prevention studies, no synergistic effect was observed with retinoids and tamoxifen. The data indicate that retinoids can potently reduce cyclin D expression levels in a variety of breast cell lines in vitro, and suggest further consideration of this mechanism for the chemoprevention of breast cancer.
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PMID:Inhibition of cyclin D expression in human breast carcinoma cells by retinoids in vitro. 923 83

To define the genetic changes of flat urothelial lesions, carcinoma in situ (CIS) and moderate dysplasias (DII) were investigated for alterations in the two chromosomal regions most frequently involved in bladder cancer. Overall, 33 CIS and 16 DII from 21 patients were used to microdissect urothelium. Dual color fluorescence in situ hybridization (FISH) using gene locus probes of 9q22 (FACC), 9p21 (CDK), 17p13 (p53), and related centromeric probes was applied on interphase nuclei. In parallel, preamplified DNA of these samples was used for loss of heterozygosity (LOH) analyses with eight microsatellite markers on chromosomes 9p, 9q and 17p, and for sequencing of exons 5-9 of p53. Data indicated nearly identical deletion frequencies for chromosomes 9 and 17 for CIS (chromosome 9, 86%; p53, 84%). DII showed a lower deletion rate in comparison with CIS (chromosome 9, 75%; p53, 53%). A very high correlation between the results of FISH and LOH analyses was found. p53 mutations were detected in 12 of 15 patients (CIS, 72%; DII, 67%). In three of 16 patients with multifocal tumors, oligoclonal lesions were identified by LOH analyses, a finding further supported by sequencing of p53, by which two different p53 deletions were detected in two cases. In conclusion, data from microdissected flat urothelial lesions indicate that chromosome 9 deletions cannot be regarded as indicators of papillary growth, because they are found frequently in both types of flat lesions of the urothelium: those associated with papillary tumors and those that are not. The similar distribution and lower amount of genetic changes in DII render DII a possible precursor lesion of CIS.
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PMID:Occurrence of chromosome 9 and p53 alterations in multifocal dysplasia and carcinoma in situ of human urinary bladder. 1183 May 37

Deregulated cell cycle and defective genome-integrity checkpoints are among the hallmarks of cancer. Here we summarize our recent studies of key components of the GI/S machinery in normal human spermatogenesis, and their abnormalities in testicular germ cell tumours (TGCTs), with special emphasis on carcinoma in situ lesions (CIS). Our combined immunohistochemical and immunoblotting analyses of normal human adult and fetal testes, CIS, seminomas, embryonal carcinomas, and teratomas, revealed an 'unorthodox' spectrum of defects within the so-called RB pathway in TGCTs. The early aberrations included lack of expression of the retinoblastoma tumour suppressor (pRB) and the CDK inhibitor pl9ink4d, and overexpression of cyclin D2. Progression from CIS to invasive TGCTswas associated with loss of another two CDK inhibitors and tumour suppressors: pl6ink4a and pl8ink4c. We also found the lack of pRB and pl9ink4d in fetal gonocytes, the candidate target cell for all types of TGCTs. These findings, together with the status of the Chk2-p53 DNA-integrity checkpoint, are considered in relation to the origin, biology and pathogenesis of TGCTs, and potential implications of the GI/S defects for the curability of these tumours.
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PMID:Deregulation of the G1/S-phase control in human testicular germ cell tumours. 1276 Mar 79

Aberrant expression of several key regulators controlling the G1/S phase of the cell cycle has been implicated in human male germ cell tumorigenesis. Given the critical role of cyclin A2 at both the G1/S and G2/M transitions and the essential role for cyclin A1 in male germ cell development, our present study focused on the involvement of the A-type cyclins in the transformation and progression of male germ cell tumors (GCTs). The expression of the A-type cyclins and their catalytic partners Cdk1 and Cdk2 was examined in all types and stages of human male GCTs, including carcinoma in situ(CIS), seminoma and non-seminoma GCTs, along with normal testis samples. Elevated levels of cyclin A2, Cdk1 and Cdk2 were detected in the majority of GCTs and were correlated with the invasiveness of the tumors (p < 0.05). Cyclin A1 expression was virtually undetectable in CIS and seminoma, but was aberrantly expressed in all non-seminomatous GCTs. Cyclin A2 expression was strongly correlated with that of its catalytic partners Cdk1 and Cdk2 in all types of testicular tumors examined (p < 0.05), whereas a strong correlation between cyclin A1 and Cdk1 or Cdk2 was only seen in non-seminomatous GCTs (p < 0.05). Histone kinase activities of cyclin A1/Cdks and cyclin A2/Cdks were found to be elevated in tumors. Our data suggest that aberrant expression of A-type cyclins and their Cdks is a significant factor in male germ cell tumorigenesis. The abundant ectopic expression of cyclin A1 in non-seminomatous GCTs and its absence in CIS and seminomas is likely linked to the tumor transformation and progression and may be relevant to clinical prognosis.
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PMID:Elevated levels and distinct patterns of expression of A-type cyclins and their associated cyclin-dependent kinases in male germ cell tumors. 1469 91

Using global gene expression analyses, multiple novel tumor markers overexpressed in infiltrating ductal adenocarcinomas of the pancreas have recently been identified. However, the expression of these markers in morphologically similar adenocarcinomas of the biliary tree has not been investigated. The purpose of the present study was 3-fold. First, we used 8 markers that have been shown to be overexpressed in whole tissue sections of pancreatic adenocarcinomas to validate tissue microarrays (TMAs) created from a series of pancreatic adenocarcinomas (n=68). The labeling patterns of 6 epithelial markers (fascin, mucin 4, 14-3-3sigma, prostate stem cell antigen, topoisomerase IIalpha, and cdc2/p34) were concordant with previously published studies on whole tissue sections, yet required far fewer slides and reagents. Mesothelin, an epithelial marker, and heat shock protein 47, a marker of peritumoral desmoplasia, showed lower levels of expression in the TMAs when compared with whole tissue sections. Second, we examined the previously unknown expression of the same 8 novel tumor proteins in cancers of the biliary tree by using TMAs created from a series of intrahepatic cholangiocarcinomas, gallbladder adenocarcinomas, and adenocarcinomas of the distal common bile duct (n=38). Each of the 8 markers was overexpressed in the biliary cancers, ranging from 14% demonstrating at least focal labeling with prostate stem cell antigen to 100% labeling with cdc2/p34. Most of the markers showed lower frequencies of expression in the biliary tract carcinomas in comparison to the pancreatic adenocarcinomas. In addition, expression patterns varied with location in the biliary system (intrahepatic versus gallbladder versus distal common bile duct). These differences were statistically significant (P<0.05) for mesothelin, mucin 4, and heat shock protein 47. Finally, the expression of selected markers in neoplastic progression of gallbladder cancer was examined. Two markers, fascin and mesothelin, showed up-regulation of expression with transition from carcinoma in situ to invasive adenocarcinoma, implicating a role for these markers in neoplastic progression. The results of this study indicate that TMA technology provides valid and cost-effective means to screen large numbers of novel tumor markers, even in tumors such as pancreatic and biliary adenocarcinomas that characteristically have abundant desmoplastic stroma. In addition, novel tumor markers of pancreatic adenocarcinomas show similar, yet not identical, expression patterns in biliary carcinomas. Therefore, these markers are potentially useful in developing diagnostic tests and treatment paradigms for tumors involving the biliary system.
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PMID:Analysis of novel tumor markers in pancreatic and biliary carcinomas using tissue microarrays. 1501 93

Amplification of chromosome band 7q21 has been frequently detected in various types of cancer including gastroesophageal junction (GEJ) adenocarcinomas. At present, no gene has been disclosed that can explain this frequent amplification of 7q21 in GEJ carcinomas. Therefore, a detailed genomic analysis of the 7q21 region was performed on a selected series of GEJ adenocarcinomas, i.e., 14 primary adenocarcinomas and 10 cell lines, by array comparative genomic hybridization (aCGH) with a 7q11.22-q31.2 contig array. A distinct peak of amplification was identified at 92.1 Mb in 7q21.2, precisely comprising cyclin-dependent kinase 6 (CDK6), a gene involved in cell cycle regulation. A smaller peak was seen at 116.2 Mb in 7q31.2, the locus of the MET proto-oncogene. No distinct peak was detected for the hepatocyte growth factor (HGF) at 81.3 Mb in 7q21.11. An immunoprofile of HGF, CDK6 and MET revealed a strong correlation between aCGH and immunohistochemical protein expression for CDK6 (P = 0.002). Furthermore, immunohistochemistry did not show expression of CDK6 in Barrett's dysplasia and carcinoma in situ, correlating expression of CDK6 with a malignant phenotype. We conclude that high-resolution genomic analysis and immunoprofiling identify CDK6 as the main candidate target for the recurrent amplification of 7q21 in GEJ adenocarcinomas.
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PMID:Molecular dissection of the chromosome band 7q21 amplicon in gastroesophageal junction adenocarcinomas identifies cyclin-dependent kinase 6 at both genomic and protein expression levels. 1843 66

Papillary lesions of the breast have an uncertain relationship to the histogenesis of breast carcinoma, and are thus diagnostically and managerially challenging. Molecular genetic studies have provided evidence that ductal carcinoma in situ and even atypical ductal hyperplasia are precursors of invasive carcinoma. However, papillary lesions have been seldom studied. We screened papillary breast neoplasms for activating point mutations in PIK3CA, AKT1, and RAS protein-family members, which are common in invasive ductal carcinomas. DNA extracts were prepared from sections of 89 papillary lesions, including 61 benign papillomas (28 without significant hyperplasia; 33 with moderate to florid hyperplasia), 11 papillomas with atypical ductal hyperplasia, 7 papillomas with carcinoma in situ, and 10 papillary carcinomas. Extracts were screened for PIK3CA and AKT1 mutations using mass spectrometry; cases that were negative were further screened for mutations in AKT2, BRAF, CDK, EGFR, ERBB2, KRAS, NRAS, and HRAS. Mutations were confirmed by sequencing or HPLC assay. A total of 55 of 89 papillary neoplasms harbored mutations (62%), predominantly in AKT1 (E17K, 27 cases) and PIK3CA (exon 20 >exon 9, 27 cases). Papillomas had more mutations in AKT1 (54%) than in PIK3CA (21%), whereas papillomas with hyperplasia had more PIK3CA (42%) than AKT1 (15%) mutations, as did papillomas with atypical ductal hyperplasia (PIK3CA 45%, AKT1 27%, and NRAS 9%). Among seven papillomas with carcinoma in situ, three had AKT1 mutations. The 10 papillary carcinomas showed an overall lower frequency of mutations, including 1 with an AKT1 mutation (in a tumor arising from a papilloma), 1 with an NRAS gene mutation (Q61H), and 2 with PIK3CA mutations (1 overlapping with the NRAS Q61H). These findings indicate that approximately two-thirds of papillomas are driven by mutations in the PI3CA/AKT pathway. Some papillary carcinomas may arise from these lesions, but others may have different molecular origins.
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PMID:High prevalence of PIK3CA/AKT pathway mutations in papillary neoplasms of the breast. 1989 24