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

The cell cycle is controlled in part by cyclin-dependent kinases (CDKs), which are activated by forming complexes with cyclins. CDKs phosphorylate certain substrates to facilitate the proliferating cells through the cell cycle. CDK inhibitors (CDKIs) such as p27 inhibit cyclin-CDK complexes and function as a negative cell cycle regulator. The overexpression of the positive regulators (cyclins) or the underexpression of the negative regulators including p27 has been seen in a variety of neoplasms, but their role and interaction in thyroid carcinogenesis is yet to be established. We studied the expression of cyclins D1 and E, and the CDKI, p27 by immunohistochemistry in 116 cases, including 59 cases of follicular variant of papillary carcinoma (FVPC) and 57 cases of follicular adenoma (FA). The positive staining was divided into four grades: 1+ if less than 10%, 2+ if 11% to 25%, 3+ if 26% to 50%, and 4+ if greater than 50% of the nuclei of tumor cells stained positively. Cyclin D1 expression was seen in 37 (63%) FVPC and 34 (60%) FA. Cyclin E-positive cells were seen in 51 (86%) FVPC and 47 (82%) FA. No significant differences in the grade of cyclins D1 (P = .261) and E (P = .284) staining was seen between FVPC and FA. Of the 59 FVPC, 53 (89%) showed p27-positive cells; of these, 33 were 1+, nine were 2+, seven were 3+ and only four were 4+ positive. Conversely, all 57 FA were p27 positive, 53 were 4+, and four were 3+ positive. This difference in the grade of p27 staining between FVPC and FA was statistically significant (P < .001). This study shows a significant underexpression of p27 in FVPC compared with FA, suggesting that a decrease in p27 expression plays a more important role than overexpression of cyclins D1 and E alone in thyroid carcinogenesis and that p27 immunostaining may be helpful in the diagnosis of FVPC.
 ...
PMID:The role of cell cycle regulatory proteins, cyclin D1, cyclin E, and p27 in thyroid carcinogenesis. 982 12

G1 phase progression of mammalian cells is mainly controlled by the cyclin-cyclin-dependent kinase (CDK)-CDK inhibitor-retinoblastoma protein (pRb) regulatory pathway. Cell cycle regulators controlling G1 phase progression are frequently involved in the carcinogenesis of many human cancer types. In hepatocellular carcinoma (HCC) the CDK inhibitor p16INK4 is predominantly inactivated by post-transcriptional regulation and p16INK4 inactivation participates in the early-stage of hepatocarcinogenesis and in disease progression. Reduced p21(WAF1/CIP1) expression, which is associated mainly with p53 gene mutation in HCCs, contributes to hepatocarcinogenesis. Reduced p27Kip1 expression is also frequently involved in HCC. The CDK inhibitors p16INK4, p21(WAF1/CIP1) and p27Kip1 are independently affected and a change in the expression of one or more of these inhibitors contributes to carcinogenesis of the majority (nearly 90%) of HCCs. Cyclin D1 amplification and overexpression play a role in the carcinogenesis of a subset (11-13%) of HCCs. Disruption of the regulatory system controlling G1 phase progression is a common event in human hepatocarcinogenesis. Further studies systematically analyzing the major regulators controlling G1 phase progression in a large cohort of HCCs will strengthen our understanding of the molecular mechanism underlying human hepatocarcinogenesis. Correcting alterations that have occurred in the G1 phase regulatory machinery may provide a novel weapon to treat and prevent HCC.
 ...
PMID:Cell cycle regulators and human hepatocarcinogenesis. 984 Jan 20

Alterations in the expression of the cell cycle regulators, cyclin D1 and cyclin-dependent kinase 4 (Cdk4), have been implicated in malignancies of both humans and experimental animal models. We hypothesize that altered expression of cyclin D1 and Cdk4 may also be involved in mouse colon tumorigenesis induced by the chemical carcinogen, azoxymethane (AOM). In the present study, SWR/J mice were given AOM by i.p. injection at a dose of 10 mg/kg once a week for 8 weeks, and colonic tissue and tumors were isolated 18 weeks later. The expression and localization of cyclin D1 and Cdk4 were examined by reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemical analyses. Cyclin D1 and Cdk4 mRNA levels in tumor samples were increased 1.3-fold (P < 0.01) and 1.2-fold (P < 0.01), respectively, when compared with control mouse colon tissue. Control colon epithelium was uniformly negative for cyclin D1 immunoreactivity, whereas minimal Cdk4 nuclear staining was confined to the lower portion of the crypts within the control tissue. Both cyclin D1 and Cdk4 immunoreactive cells were markedly increased in preneoplastic lesions and in adenomas isolated from AOM-treated mice. Furthermore, some morphologically normal colon crypts from AOM-treated mice showed positive cyclin D1 immunoreactivity. These findings suggest that overexpression of cyclin D1 and Cdk4 occurs early in the AOM-induced mouse colon tumorigenesis and may contribute to tumor progression in this model.
Carcinogenesis 1998 Nov
PMID:Altered expression of cyclin D1 and cyclin-dependent kinase 4 in azoxymethane-induced mouse colon tumorigenesis. 985 16

Cyclin D1 protein plays an important part in regulating the progress of the cell during the G1 phase of the cell cycle. The cyclin D1 gene, CCND1, is amplified in approximately 20% of mammary carcinomas, and the protein is over-expressed in approximately 50% of cases. This has led to intensive study to ascertain whether cyclin D1 is a biological marker in breast cancer; however, the clinical work has produced unexpected results. Work in cell lines and in transgenic mice indicate that CCND1 is a weak oncogene and it was expected that, like c-erbB-2, over-expression of cyclin D1 protein would be associated with a poor prognosis. Early immunohistochemical prognostic studies produced equivocal results but we, and others, have recently shown that strong staining for cyclin D1 is more likely to be seen in well differentiated, estrogen receptor positive carcinomas. Furthermore, we have found that over-expression of cyclin D1 is actually associated with a good outcome, both in terms of prognosis and response to endocrine treatment. Cyclin D1 is frequently over-expressed in ductal carcinoma in situ but not in benign breast disease, including atypical ductal hyperplasia; hence its expression appears to be closely linked with carcinogenesis. In order to help explain the apparent beneficial effects of cyclin D1 over-expression, a number of closely associated cell cycle proteins have also been evaluated, including the cyclin dependent kinase inhibitor p27, which blocks the activating effects of cyclin D1. Initial reports show that high levels of p27 are associated with a good prognosis and we have shown a positive association between p27 and cyclin D1 expression. These clinical results of cyclin D1 are an example of how information obtained from basic cell biology studies needs to be complemented by clinical studies to ascertain the true worth of a prognostic marker.
 ...
PMID:Cyclin D1 in breast cancer. 1006 68

Overexpression of cyclin D1 protein is observed in the majority of breast cancers, suggesting that dysregulated expression of cyclin D1 might be a critical event in breast cancer carcinogenesis. We investigated whether retroviral-mediated expression of cyclin D1 might affect all-trans-retinoic acid (ATRA)-mediated growth inhibition and differentiation of normal cultured human mammary epithelial cells (HMECs). HMECs treated with 1.0 microM ATRA undergo irreversible growth inhibition starting at 24 h and complete G0/G1-phase arrest by Day 3. Cyclin D1 protein levels are observed to decrease in association with the initiation of growth arrest starting at 24 h and then increase by approximately 35% on Day 3. Concomitant with this observed increase in cyclin D1, HMECs undergo morphologic changes consistent with progression to a more differentiated phenotype, including an increase in cell size, increased cell spreading, increased tonofilaments, and accumulation of cytoplasmic vesicles containing lipid. Dysregulated expression of cyclin D1 in HMECs results in inhibition of G0/G1-phase arrest mediated by ATRA. In addition, HMECs expressing exogenous cyclin D1 are resistant to differentiation by ATRA. Our results suggest that coordinated expression of cyclin D1 may be critical for normal mammary epithelial cell homeostasis, and dysregulated expression of cyclin D1 might result in retinoid resistance and promote mammary carcinogenesis.
 ...
PMID:Dysregulated expression of cyclin D1 in normal human mammary epithelial cells inhibits all-trans-retinoic acid-mediated G0/G1-phase arrest and differentiation in vitro. 1032 55

Increased protein expression of the G1 cyclins D1 and E is reported in invasive non-small cell lung carcinoma. However, during transformation of the bronchial epithelium, overexpression of these species occurs, and their relationship to aberrant expression of p53 and retinoblastoma (Rb) has not been described previously. To determine the expression of these cell cycle regulators during the development of invasive squamous cell carcinoma (SCC) of the lung, the immunohistochemical expression patterns in normal bronchial epithelium (n = 36), squamous metaplasia (SM; n = 28), and epithelial atypia (n = 34) were compared with that in low-grade dysplasia (LGD; n = 17), high-grade bronchial dysplasia (HGD; n = 30), and SCC (n = 36). Monoclonal anti-p53 Pab1801, polyclonal anti-cyclin D1 DCS6, monoclonal anti-cyclin E HE12, and monoclonal anti-Rb OP-66 antibodies were used. Cyclin D1 was not expressed in normal bronchial epithelium but was detected in 7% of SMs, 15% of atypias; 18% of LGDs, 47% of HGDs, and 42% of SCCs. Cyclin E was not detected in normal epithelium (n = 24), SM (n = 16), or LGD (n = 12), but it was found in 9% of atypias (2 of 22), 33% of HGDs (7 of 21), and 54% of SCCs (13 of 24). p53 was not expressed in normal epithelium, SM, and LGD, but it was overexpressed in 6% of atypias, 53% of HGDs, and 61% of SCCs. Abnormal Rb expression was found only in 2 of 36 cases of SCC. A total of 91% of HGDs and 92% of SCCs exhibited overexpression of at least one of the p53, cyclin D1, or cyclin E species. However, no link was observed between overexpression of p53 and the overexpressed G1 cyclins in preneoplastic lesions. Overexpression of cyclin D1, cyclin E, and p53 occurs frequently and independently in pulmonary SCC and is detected in lesions before the development of invasive carcinoma. In contrast, altered Rb expression is a late and infrequent event in squamous cell carcinogenesis.
 ...
PMID:Overexpression of cyclins D1 and E is frequent in bronchial preneoplasia and precedes squamous cell carcinoma development. 1034 60

The peroxisome proliferators are rodent non-genotoxic hepatocarcinogens that suppress apoptosis and induce DNA replication, cell proliferation and liver tumours. In order to investigate the effect of peroxisome proliferators on cell cycle progression, we arrested the well-differentiated rat hepatoma cell line FaO in the G1 phase of the cell cycle. Under these conditions, CDK2 and CDK4 protein expression remained unchanged compared with proliferating cells, but expression of cyclin D1 and p27(KIP1) was down-regulated and cyclin E accumulated in the inactive form. G1-arrested cells were able to enter the cell cycle on addition of exogenous growth factors such as epidermal growth factor (EGF) or hepatocyte growth factor (HGF) and replicate their DNA within 12 to 24 h of re-stimulation. Upon release from G1 arrest, CDK2 protein expression was down-regulated and, surprisingly, p27(KIP1) expression was restored. Cyclin D1 and phosphorylated cyclin E accumulated at 12 h but were degraded by 24 h after addition of EGF. Importantly, the peroxisome proliferator nafenopin and tumour necrosis factor alpha were able to induce DNA replication. Thus, the profile of expression of cell cycle regulatory proteins upon stimulation with nafenopin is comparable with that induced by growth factors such as EGF.
Carcinogenesis 1999 Jul
PMID:G1-arrested FaO cells re-enter the cell cycle upon stimulation with the rodent non-genotoxic hepatocarcinogen nafenopin. 1038 91

Cyclin D1 is a cell cycle regulator which is overexpressed in a variety of human cancers. We examined overexpression of cyclin D1 in several stages of rat colorectal carcinogenesis induced by azoxymethane (AOM) treatment. The level of cyclin D1 in 13 aberrant crypt foci (ACF) (atypical hyperplasias), 22 colorectal tumors (14 non-invasive adenocarcinomas and eight invasive adenocarcinomas) was assessed by immunostaining using a polyclonal antibody. Cell proliferation of these samples was investigated by measurement of 5-bromo-2'-deoxyuridine-labeling index. Indices of cyclin D1-positive cells in adenocarcinomas and atypical hyperplasias were significantly higher than that in normal crypts (P < 0.05). Moreover, cyclin D1-positive rates in the two types of adenocarcinomas were significantly higher than that in atypical hyperplasias (P < 0.05). Staining of nuclear cyclin D1 was very strong in almost all adenocarcinomas and four ACF. Comparisons of BrdU-positive indices in colorectal lesions showed similar results to the cyclin D1-positive indices. These results suggested that overexpession of cyclin D1 occurs early in the multistep carcinogenesis, and plays an important role in rat colorectal carcinogenesis.
 ...
PMID:Expression of the cyclin D1 gene in rat colorectal aberrant crypt foci and tumors induced by azoxymethane. 1040 47

Alterations in the expression of cyclin D1 have been reported frequently in several human cancers, but their significance in the multistep model of carcinogenesis has been scantly described. To define the pattern of cyclin D1 expression in the development of ovarian cancer and clinical outcome, 55 cases of benign ovarian tumors, 12 borderline cases, and 37 ovarian carcinomas (32 primary and 5 recurrent carcinomas) were studied. Analyses were carried out on fresh tumor specimens by Western blotting and reverse transcription-PCR and provided significant superimposable results (P = 0.00001). Cyclin D1 abundance was classed according to the densitometric values as undetectable, detectable, well detectable, and highly detectable. A significant increase (P < 0.000001) in median cyclin D1 values was observed from benign (0.038; range, 0.001-0.705) to borderline (0.226; range, 0.001-0.623) to malignant (0.347; range, 0.027-2.330) to recurrent (0.887; range, 0.309-2.2260) tumors. In addition, higher median cyclin D1 values were reported in serous carcinomas (P = 0.058) and advanced-stage diseases (P = 0.003). Survival analyses carried out in the 32 primary carcinomas showed no significant difference in overall survival between detectable versus well/highly detectable cyclin D1 neoplasms. Conversely, a significant relationship between cyclin D1 expression and progression-free survival was found (P = 0.031). These results may elucidate the function of altered cyclin D1 expression in ovarian tumorigenesis and provide a basis for additional studies on its prognostic role.
 ...
PMID:Increased cyclin D1 expression is associated with features of malignancy and disease recurrence in ovarian tumors. 1043 89

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


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