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)

Alterations in the Rb pathway have been described in many different tumors. In order to study this cell cycle regulatory mechanism in murine T cell lymphomas, we have analyzed the RNA and protein expression of the cyclin D1, cdk4 and retinoblastoma genes in primary tumor samples. We have detected overexpression of the cyclin D1 gene and deficient expression of the retinoblastoma gene in 42 and 28% of these tumors, respectively. The immunohistochemical analysis showed that these RT-PCR results are correlated with a significant increase in the number of positive cells for cyclin D1 and a moderate decrease in the expression of Rb protein, respectively. The analysis of cyclin D1, Rb, p15(INK4b) and p16(INK4a) showed that 75% of lymphomas had alterations in these genes and indicates that the Rb pathway is frequently altered in mouse primary T cell lymphomas. Moreover, 31% of lymphomas presented simultaneous alterations in at least two of these genes, suggesting the importance of concurrent alteration of different Rb pathway regulators. In addition, we have characterized these samples for mutational status of the N-ras and K-ras genes. We have only detected mutations in codon 12 of K-ras in six of 49 lymphomas (12%). Interestingly, five of these lymphomas also showed alterations in at least one of the Rb pathway regulators analyzed here. Taken together, these data suggest that deregulation of the Rb pathway regulators and/or oncogenic activation of K-ras may represent a common important clue in progression of murine T cell lymphomas.
Carcinogenesis 1999 Sep
PMID:Cooperative alterations of Rb pathway regulators in mouse primary T cell lymphomas. 1046 10

UV-radiation is a major risk factor for non-melanoma skin cancer causing specific mutations in the p53 tumor suppressor gene and other genetic aberrations. We here propose that elevated temperature, as found in sunburn areas, may contribute to skin carcinogenesis as well. Continuous exposure of immortal human HaCaT skin keratinocytes (possessing UV-type p53 mutations) to 40 degrees C reproducibly resulted in tumorigenic conversion and tumorigenicity was stably maintained after recultivation of the tumors. Growth at 40 degrees C was correlated with the appearance of PARP, an enzyme activated by DNA strand breaks and the level corresponded to that seen after 5 Gy gamma-radiation. Concomitantly, comparative genomic hybridization (CGH) analyis demonstrated that chromosomal gains and losses were present in cells maintained at 40 degrees C while largely absent at 37 degrees C. Besides individual chromosomal aberrations, all tumor-derived cells showed gain of chromosomal material on 11q with the smallest common region being 11q13.2 to q14.1. Cyclin D1, a candidate gene of that region was overexpressed in all tumor-derived cells but cyclinD1/cdk4/cdk6 kinase activity was not increased. Thus, these data demonstrate that long-term thermal stress is a potential carcinogenic factor in this relevant skin cancer model, mediating its effect through induction of genetic instability which results in selection of tumorigenic cells characterized by gain of 11q.
 ...
PMID:Tumorigenic conversion of immortal human skin keratinocytes (HaCaT) by elevated temperature. 1052 43

Disruption of the cell-cycle regulation through over-expression or mutation of cyclins and cyclin-dependent kinases has been implicated in carcinogenesis. In order to determine whether keratoacanthoma (KA) is unique or a variant of squamous cell carcinoma (SCC) and whether expression of mitosis-related antigens are associated with KAs' tendency to regress, we compared the immunohistochemical expression of mitotic cyclins (cyclins A and B) and their cyclin-dependent kinase p34(cdc2) in 21 KAs, 8 regressing KAs, and 28 conventional squamous cell carcinomas. KAs showed both overlap and significant differences in expression of these mitosis-related antigens compared to SCCs. Basal and parabasal pattern of expression of cyclins A and B significantly predominated in KAs in contrast to SCCs which exhibited diffuse pattern (cyclin A 86%/cyclin B 64% vs. 25%/36%, p < 0.01). However, no differences in the highest mean level of expression in 'hot spot' loci of cyclins A and B were identified comparing KAs to SCCs (19%/12% vs. 25%/13%, p > 0.05). For the cyclin-dependent kinase p34(cdc2), no differences in pattern, distribution or mean levels of expression were found. For cyclins A and B, regressing KA showed significantly more regional tumor labeling (88%/88% vs. 57%/33%, p = 0.03) and a lower mean level of immunoreactivity (5%/4% vs. 19%/12%, p = 0.001) compared to mature KAs. These findings indicate a role for mitotic cyclins in the evolution of both SCC and KA. The overlapping patterns of expression for these mitosis-related antigens suggest that KAs represent a variant of SCC that exhibit an overwhelming but not absolute tendency to involute.
 ...
PMID:Comparison of mitotic cyclins and cyclin-dependent kinase expression in keratoacanthoma and squamous cell carcinoma. 1055 11

Understanding the process of carcinogenesis is key to developing therapies which might interrupt or reverse tumor onset and progression. Cell growth and death signals are dependent not only upon molecular mechanisms within a cell but also upon external stimuli such as hormones, cell - cell signaling, and extracellular matrix. Mouse models can be used to dissect these complex processes, to identify key signaling pathways operating at different stages of tumorigenesis, and to test the strength of specific interventions. In the WAP-TAg mouse model, carcinogenesis is initiated by expression of the Simian Virus 40 T antigen (TAg). TAg expression is triggered by hormonal stimulation, either during estrus or pregnancy. Breast adenocarcinomas (ranging from well to poorly differentiated) develop in 100% of the female mice by approximately 8 - 9 months of age. Three distinct stages of tumorigenesis are easily identified: an initial proliferation, hyperplasia, and adenocarcinoma. The mean time to first palpable tumor in mice which undergo at least one pregnancy is 6 months. The tumorigenic process is marked by a competition between proliferation and apoptosis and is characterized by cellular acquisition of genetic mutations and increased stromal fibrosis. Protein levels of cell cycle control genes cyclin D1, cdk2, and E2F-1 are increased in these adenocarcinomas. c-Fos protein levels are slightly increased in these cancers, while c-Jun levels do not change. Hormonal exposure alters progression. Estrogen plays a role during the early stages of oncogenesis although the growth of the resulting adenocarcinomas is estrogen-independent. Transient hormonal stimulation by glucocorticoids that temporarily increases the rate of cell proliferation results in tetraploidy, premature appearance of irreversible hyperplasia, and early tumor development. Tumor appearance also can be accelerated through over expression of the cell survival protein, Bcl-2. Bcl-2 over expression not only reduces apoptosis during the initial proliferative process but also decreases the total rate of cell proliferation. This block in cell proliferation is lost selectively as the cells transition to adenocarcinoma. The WAP-TAg model can be utilized to investigate how the basic processes of cell proliferation, apoptosis, DNA mutation, and DNA repair are modified by external and internal signals during mammary oncogenesis.
 ...
PMID:WAP-TAg transgenic mice and the study of dysregulated cell survival, proliferation, and mutation during breast carcinogenesis. 1071 84

p21 (p21WAF1/CIP1) is involved in cell cycle regulation, as an inhibitor of cyclin dependent kinases (CDK2, CDK4 and CDK6). However, subsequent in vitro studies have suggested that p21 may influence this process by an additional mechanism, in particular through the regulation of cyclin D1 subcellular localisation. This study of primary resectable non-small cell lung cancer (NSCLC) was designed to examine p21 functions in association with the expression of cyclin D1 (including its subcellular localisation), p16INK4a and pRb. p21 expression was examined in 50 NSCLC (stage I-IIIA) and in several normal lung samples all of which had previously been studied for cyclin D1 (DNA, RT-PCR, immunostaining), p16INK4a (DNA, RT-PCR, immunostaining), and pRb (immunostaining). As assessed by immunoblotting and immunostaining, p21 was expressed at low levels in normal lung tissue with immunoreactivity seen in a small number of bronchial epithelial cells only. In NSCLC, p21 expression (> or =10% of positive cells) was observed in 42% (21/50) of cases. High p21 expression was associated with well differentiated tumours (p = 0.01) and cyclin D1 nuclear staining (p = 0.02). Furthermore, we found an inverse correlation with p16INK4a (p = 0.004) and a direct correlation with pRb expression (p = 0.02). Risk of relapse was associated with p16INK4a and p21 status with no relapse in patients with normal p16INK4a and p21. Our results confirm that a large number of NSCLC have a low level of p21 expression. The associations of p21 and nuclear cyclin D1, pRb, p16INK4a support the relevance of pathways linked to lung carcinogenesis that involve p21 but may act in addition to direct CDK inhibition.
 ...
PMID:p21 is associated with cyclin D1, p16INK4a and pRb expression in resectable non-small cell lung cancer. 1076 31

We performed the immunohistochemical staining for six G1 check point cell cycle proteins to study their expression patterns and roles in the gastric carcinogenesis. We studied 76 cases of paraffin blocks that included the sections of 18 tubular adenomas (TA), 38 early gastric carcinomas (EGC) (20 cases of mucosal type, nine cases of submucosal type with no nodal metastasis, nine cases of submucosal type with nodal metastasis), 20 advanced gastric carcinomas (AGC) (ten cases with no nodal metastasis, ten cases with nodal metastasis). We found that abnormal expression of p16 and p27 increased with the progression of tubular adenomas to advanced gastric cancers. Inverse relationship between pRb and p16 proteins was found in a small portion of the gastric tumors. Expressions of pRb and cdk4 were consistently high in benign and malignant gastric tumors. Expression of cyclin D1 and cyclin E rather decreased with the tumor progression. In conclusion, losses of p16 and p27 seem to play a significant role during the gastric carcinogenesis, and the G1 checkpoint cell cycle proteins such as pRb, cdk4, cyclin D1, and cyclin E variably participate in the gastric carcinogenesis and metastasis by the mechanisms which are yet unknown; thus, further studies need to be performed to elucidate the mechanisms.
 ...
PMID:Loss of p16 and p27 is associated with progression of human gastric cancer. 1077 41

Human papillomavirus (HPV) survives by reactivating DNA replication in post-mitotic cells. In the present study, we describe a mouse model of HPV-dependent disease. In these mice, DNA synthesis is activated in suprabasal keratinocytes, leading to acanthosis, parakeratosis and enhanced desquamation. The full-length E6/E7 transcript and two alternately spliced products are produced and in most lines the predominant product is E6*. In the present study, we examine the effects of E6/E7 on cell cycle regulatory protein expression. E6/E7 expression in mouse epidermis is correlated with increased levels of the p53, p21, p27, cdk2, cdk4, cdk6, cyclin D1 and cyclin E regulatory proteins. Hyperproliferation is also observed in the buccal mucosa and the tongue epithelia of E6/E7 mice, and p53 levels are markedly increased in these epithelia. These results suggest that the major changes in cell cycle regulatory protein expression are in response to the presence of E7 and that E6 has a lesser impact.
Carcinogenesis 2000 May
PMID:Suprabasal expression of the human papillomavirus type 16 oncoproteins in mouse epidermis alters expression of cell cycle regulatory proteins. 1078 29

Previous studies from our laboratory demonstrated that diallyl disulfide (DADS), an oil-soluble allyl sulfur compound found in processed garlic, markedly suppressed p34(cdc2) kinase activity and induced a G(2)/M phase arrest in cultured human colon tumor (HCT-15) cells. The present studies reveal that suppression of p34(cdc2) kinase activity by DADS does not result from direct interactions with the protein, but through changes in factors influencing the formation and conversion of the enzyme to its active form. Flow cytometric analyses showed that the increased proportion of cells in the G(2)/M phase following DADS treatment was accompanied by an increase in cyclin B(1) protein expression. A temporal and dose-dependent response in cyclin B(1) expression was observed in cells treated with DADS. Western blot analysis revealed that 50 microM DADS did not influence the quantity of p34(cdc2) protein expressed, but did decrease the amount associated with cyclin B(1) by 26% (P < 0.05). Exposure of unsynchronized cells to 25 or 50 microM DADS caused a trend towards increased p34(cdc2) hyperphosphorylation (17 and 22%, respectively). Exposure of synchronized cells to 100 microM DADS increased p34(cdc2) hyperphosphorylation by 15% (P < 0.05). Consistent with its ability to slightly increase the quantity of hyperphosphorylated p34(cdc2), DADS, 25 or 50 microM, decreased cdc25C protein expression by 23 and 46%, respectively (P < 0.05). The present studies suggest that the ability of DADS to inhibit p34(cdc2) kinase activation occurs because of decreased p34(cdc2)/cyclin B(1) complex formation and modest p34(cdc2) hyperphosphorylation.
Carcinogenesis 2000 Jun
PMID:Diallyl disulfide inhibits p34(cdc2) kinase activity through changes in complex formation and phosphorylation. 1083

Cyclin-dependent kinase inhibitors (CDKI) are negative regulators of cell cycle progression by binding the cyclin-CDK complex and inhibiting the CDK activity. Genetic alteration in the CDKI genes has been implicated for carcinogenesis. To test the genetic alteration in the p27 and p57 genes, KIP family CDKI genes, 30 gastric tumor-normal pairs and 8 gastric cancer cell lines were analyzed for mutations by polymerase chain reaction-single strand conformational polymorphism (PCR-SSCP). No mutation was detected in these genes although length polymorphisms in the proline-alanine repeat of the p57 gene were detected. When the p27 and p57 mRNAs were analyzed in gastric cancer cell lines by RT-PCR, the p27 mRNA was expressed considerably high in tumor cells but expression of the p57 mRNA was much low in gastric cancer cell lines compared to that of normal cells. The result suggests that inactivation of gene expression rather than mutations in the p57 gene accounts possibly for the involvement of this gene in tumorigenesis of gastric cancer. However, expression of the p27 gene seems to be essential for cell survival.
 ...
PMID:Mutation and expression of the p27KIP1 and p57KIP2 genes in human gastric cancer. 1092 19

Epidemiological and clinical data suggest that selenium may prevent prostate cancer, but the biological effects of selenium on normal or malignant prostate cells are not well known. We evaluated the effects of sodium selenite (Na2SeO3) or l-selenomethionine (SeMet) on monolayer and anchorage-independent growth in a series of normal primary prostate cultures (epithelial, stromal, and smooth muscle) and prostate cancer cell lines (LNCaP, PC-3, and DU145). We observed differential, dose-dependent growth inhibition and apoptosis within prostate cancer cells (compared with normal prostate cells) treated with 1-500 microM of Na2SeO3 or SeMet. Na2SeO3 more potently inhibited growth at any given concentration. The androgen-responsive LNCaP cells were the most sensitive to selenium growth suppression (IC50s at 72 h for Na2SeO3 and SeMet were 0.2 and 1.0 microM, respectively). Growth of the primary prostate cells virtually was not suppressed (IC50s at 72 h for Na2SeO3 and SeMet were 22-38 and >500 microM, respectively). We also observed that DNA condensation and DNA fragmentation (terminal deoxynucleotidyltransferase dUTP nick end labeling/fluorescence-activated cell sorting) were elevated in selenium-treated cells and that activated caspase-3 colocalized with terminal deoxynucleotidyltransferase dUTP nick end labeling-stained cells by immunofluorescence. Higher basal poly(ADP-ribose) polymerase (PARP) expression levels and PARP cleavage (a substrate for caspase-3) were observed during apoptosis in tumor cells, compared with normal cells. Selective tumor cell death was associated with an increase in sub-G0-G1 cells after propidium iodide staining and fluorescence-activated cell sorting analysis. SeMet caused an increase in arrest in the G2-M phase of the cell cycle selectively in cancer cells. Inhibition of cancer cell growth by SeMet was associated with phosphorylation of P-Tyr15-p34/cdc2, which caused growth arrest in the G2-M phase. Anchorage-independent growth of prostate cancer cells in soft agar was sensitive to selenium. Our results suggest that Na2SeO3 is the more potent inducer of apoptosis in normal and cancer prostate cells. Our SeMet results involving PARP and G2-M cell-cycle arrest (cited above) indicate that SeMet selectively induces apoptosis in cancer but not primary cells of the human prostate. Our overall findings are relevant to the molecular mechanisms of selenium actions on prostate carcinogenesis and help demonstrate the selective, dose-dependent effects of selenium (especially SeMet) on prostate cancer cell death and growth inhibition.
 ...
PMID:Selenium effects on prostate cell growth. 1109 24


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>