Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Protein complexes containing cyclins and cyclin-dependent protein kinases (cdks) have been shown to be rearranged in both spontaneous and viral tumor antigen-transformed cells. We have examined G1- and S-phase cyclin/cdk complexes as a function of the neoplastic progression of human diploid fibroblasts transfected with the SV40 large T antigen. We find that the expression of cyclin D1 and its association with proliferating cell nuclear antigen (PCNA) and Waf1 remain unchanged in precrisis human fibroblasts transfected with SV40 large T antigen. However, in these same cells the association of cdk4 with cyclin D1, PCNA, and Waf1 is disrupted. Upon immortalization, cyclin D1 protein expression is decreased, and binding of both PCNA and Waf1 with the remaining cyclin D1 is reduced. In contrast, large T antigen increased the expression of cyclin A and cyclin E proteins in both precrisis and immortal cells and did not reduce the binding of PCNA or Waf1 to either cdk2 or cyclin A proteins. These results show that large T-antigen expression in human fibroblasts selectively uncouples cyclin D1 from cdk4, and subsequent immortalization of these cells results in additional changes to the cyclin D1-dependent cell cycle regulatory pathways.
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PMID:Immortalization of human fibroblasts by SV40 large T antigen results in the reduction of cyclin D1 expression and subunit association with proliferating cell nuclear antigen and Waf1. 755 44

p21/WAF1/CIP1/SDI1 is an important cell-cycle mediator with tumor suppressor gene capabilities, and its inactivation could potentially lead to tumor progression. Because tumor suppressor genes are commonly inactivated by somatic and germline mutations, we analyzed a variety of human tumor cell lines for p21 mutations. We used single-strand conformational analysis and direct sequencing to identify possible mutations in the p21 coding region. Two base-alterations were observed in 41 immortalized human tumor cell lines. A previously reported polymorphism that results in a serine-to-arginine amino-acid substitution at codon 31 was found in 24% (10 of 41) of the tumor cell lines but was also found in 10% (six of 62) of normal parental DNAs tested and 7% (three of 43) of normal DNAs from patients with primary endometrial tumors. Another nucleotide substitution found at codon 80 resulted in the replacement of threonine with methionine. Codon 80 changes were found in 7% (three of 41) of the tumor cell lines (all endometrial) and in 2% (one of 62) of the normal parental DNAs. This change was not found in any of the primary endometrial tumors examined. The biological activity of these base changes was analyzed by using in vitro cyclin-dependent kinase 2-cyclin A kinase assays and calcium phosphate transfections. We observed that wild-type p21 and the p21 variants had similar growth-inhibitory abilities. Thus, our results suggest that mutation of the p21 gene is not prevalent in human tumor cell lines and is not a probable mechanism of inactivation of this gene.
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PMID:Mutational analysis of the p21/WAF1/CIP1/SDI1 coding region in human tumor cell lines. 878 65

The differences in the protein expression of cyclins, cyclin-dependent kinases (cdks), and their inhibitors and cdk kinase activities were examined in serum dependent (SD) and independent (PF) clones of the murine fibrosarcoma cell line, Gc-4. The expression of cyclin A in SD was minimal in contrast to PF. Furthermore, cdk2 kinase activity in PF was remarkably lower than that in SD, yet the G1/S transition in PF appeared normal. PF was also resistant against the selective inhibitor of cdk2, butyrolactone I. These findings suggest that tumor cell proliferation and tumor progression can be promoted by the activation of a molecule(s) downstream of cdk2.
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PMID:Cell cycle control with minimal participation of Cdk2 in a murine fibrosarcoma clone cultured in protein-free medium. 912 24

The product of the c-mos proto-oncogene is a protein kinase that is normally expressed in germ cells and functions during oocyte maturation. It has been shown, however, that inappropriate expression of either the viral or cellular mos gene can induce neoplastic progression in somatic cells. Furthermore, v-mos-transformed NIH3T3 cells will undergo arrest of proliferation in early G1 upon serum withdrawal but are unable to appropriately down-regulate cell cycle regulatory proteins, such as cyclin and cdc2 proteins, that normally are down-regulated in quiescent, untransformed NIH3T3 cells. Since the levels of these proteins are partially transcriptionally controlled, we investigated whether there were alterations in the expression of E2F and AP-1 transcription factor complexes. Indeed, the putative G0/G1-specific p130-E2F complex that is normally observed during low serum-induced cell cycle arrest in NIH3T3 cells is not present in serum starved v-mos-transformed cells. Instead, G1-phase arrested v-mos-transformed cells stably express two E2F protein complexes that are normally observed only during S-phase in untransformed cells. The elevation of these complexes in arrested v-mos-transformed cells may be the cause of the transcriptional activation of the E2F-regulated genes cdc2, DHFR, cyclin A, and E2F1 seen in serum starved v-mos-transformed cells. In addition, there are high levels of AP-1 DNA binding activity in serum starved v-mos-transformed cells compared to very low amounts in nontransformed cells. This altered regulation of transcription factor complexes and cell cycle control proteins upon serum withdrawal may provide a mechanism for the uncontrolled cell growth associated with neoplastic transformation induced by certain proto-oncogenes.
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PMID:Deregulation of specific E2F complexes by the v-mos oncogene. 922 66

The expression of cyclin A protein was retrospectively investigated in 124 patients with human esophageal squamous cell carcinoma with immunohistochemical techniques using antibody to cyclin A protein (BF683). Of 124 tumors, 49 (39.5%) exhibited positive staining in cancer cells with this antibody. Staining was observed predominantly but not exclusively in the nucleus. A significantly higher degree of association of immunoreactivity with this antibody was detected for advanced types of tumors (stages I, II, III, and IV) than for early tumors (stage 0; P < 0.05). Patients with cyclin A immunopositivity had a significantly poorer survival rate than did other patients (P < 0.01). These findings provide the first evidence for frequent and unscheduled overexpression of cyclin A protein in human esophageal cancer and suggest the possibility that alteration of cyclin A overexpression is associated with tumor progression and patient prognosis for esophageal cancers.
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PMID:Determination of the prognostic significance of unscheduled cyclin A overexpression in patients with esophageal squamous cell carcinoma. 981 30

Our aim was to analyze the relationship between the proliferative activity of cancer cells, assessed using some cell cycle markers, and clinicopathological factors in colorectal carcinoma patients. Immunostaining for Ki-67 (pan-cell cycle marker), cyclin D1 (G1-phase marker) and cyclin A (S- to G2-phase marker), and in situ hybridization for histone H3 mRNA (S-phase marker) were carried out. Immunoreactivity was evaluated semiquantitatively using a scoring system to calculate a staining index (SI). The expression of cyclin D1, histone H3 mRNA and cyclin A correlated significantly with Ki-67 antigen expression. The SIs of Ki-67, cyclin A and histone H3 mRNA were significantly higher in patients > or = 65 years of age than in those < 65. The SIs of Ki-67 and cyclin D1 in poorly differentiated adenocarcinomas were significantly higher than in the other tumor types. Furthermore, the SI of cyclin D1 in carcinomas with lymph node metastasis was higher than in carcinomas without metastasis and was higher in advanced carcinomas than early carcinomas. The overall survival was significantly lower in patients with cyclin A overexpression than in those without. Multivariate analysis indicated that cyclin A overexpression is an independent prognostic factor in patients with colorectal adenocarcinoma. Our results indicate that cyclin D1 overexpression correlates with poor adenocarcinoma differentiation and tumor progression, and cyclin A overexpression is a superior indicator of poor prognosis compared with the other cell cycle markers tested.
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PMID:Expression of cell cycle markers in colorectal carcinoma: superiority of cyclin A as an indicator of poor prognosis. 1037 38

Galectin-3 is a member of a growing family of animal beta-galactoside-binding proteins shown to be involved in cell growth, differentiation, apoptosis resistance, and tumor progression. In the present study, we investigated whether galectin-3 can protect against apoptosis induced by the loss of cell anchorage (anoikis). Because studies suggest that cellular sensitivity to anoikis is associated with cell cycle regulation, we examined the role of galectin-3 on cell cycle regulation. Although BT549 cells (human breast epithelial cells) undergo anoikis, galectin-3-overexpressing BT549 cells respond to the loss of cell adhesion by inducing G1 arrest without detectable cell death. Galectin-3-mediated G1 arrest involves down-regulation of G1-S cyclin levels (cyclin E and cyclin A) and up-regulation of their inhibitory protein levels (p21(WAF1/CIP1) and p27KIP1). After the loss of cell anchorage, Rb protein becomes hypophosphorylated in galectin-3-overexpressing cells, as predicted from the flow cytometric analysis and immunoblot analysis of cyclins and their inhibitors. Interestingly, galectin-3 induces cyclin D1 expression (an early G1 cyclin) and its associated kinase activity in the absence of cell anchorage. On the basis of these results, we propose that galectin-3 inhibition of anoikis involves cell cycle arrest at an anoikis-insensitive point (late G1) through modulation of gene expression and activities of cell cycle regulators. The present study suggests that galectin-3 may be a critical determinant for anchorage-independent cell survival of disseminating cancer cells in the circulation during metastasis.
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PMID:Cell cycle arrest and inhibition of anoikis by galectin-3 in human breast epithelial cells. 1046 21

Using single and double transgenic mouse models, we investigated how c-Myc modulates the mammary epithelial cell cycle to induce cancer and how TGFalpha enhanced the process. In c-myc transgenic mice, c-myc expression was high in the hyperplastic mammary epithelium and in the majority of tumor areas. However, the tumors displayed focal areas of low expression of c-myc but high rates of proliferation. In contrast to E2F1 and cyclin A2, which were induced and co-localized with c-myc expression, induction of cyclins D1 and E occurred only in these tumor foci. Overexpression of cyclin D1 also occurred in the hyperplastic epithelium of tgfalpha-single and tgfalpha/c-myc-double transgenic mice. In tgfalpha/c-myc tumors, cells positive for cyclins D1 and E were randomly spread, without showing a reciprocal relationship to c-myc expression. In contrast to c-myc tumors, most tgfalpha/c-myc tumors showed undetectable levels of retinoblastoma protein (pRB), and the loss of pRB occurred in some cases at the mRNA level. These results suggest that E2F1 and cyclin A2 may be induced by c-Myc to mediate the onset of mammary cancer, whereas overexpression of cyclins D1 and E may occur later to facilitate tumor progression. TGFalpha may play its synergistic role, at least in part, by inducing cyclin D1 and facilitating the loss of pRB.
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PMID:Cell cycle basis for the onset and progression of c-Myc-induced, TGFalpha-enhanced mouse mammary gland carcinogenesis. 1071 72

Traditional prognostic indicators for astrocytic tumors include tumor size, type, and histologic grade. Data suggest that tumor growth fraction assessed by MIB-1 is an important predicator of survival. Cyclin A, like MIB-1, is a recently described specific marker of proliferation, detectable primarily in S phase of the cell cycle as it undergoes progression to G2 phase. Thirty-seven cases of astrocytic tumors--14 cases of World Health Organization grade 1 and 2 (low grade tumors), 8 cases of grade 3 (anaplastic astrocytoma), and 15 cases of grade 4 (glioblastoma multiforme)--were simultaneously evaluated using routine paraffin immunohistochemical methods with commercial antibodies against MIB-1 and cyclin A. The results were quantitated using a Cell Analysis System (CAS) 200 image analyzer. The mean percentage positive nuclear area for MIB-1 was 3.32% in grade 1 and 2, 19.27% in grade 3, and 24.00% in grade 4 astrocytic tumors. Cyclin A showed a similar pattern of positivity in the same cases: 2.84% in grade 1 and 2, 16.27% in grade 3, and 24.88% in grade 4 astrocytic tumors. The data suggest that both proliferation markers correlated significantly with histologic grade. Cyclin A appears to be as good an indicator of brain tumor proliferation as MIB-1. Because cyclin A is detectable primarily in the S phase of the cell cycle, the fraction of cells positive for cyclin A should allow for a more accurate indicator of tumor progression.
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PMID:Comparison of cyclin A and MIB-1 expression in astrocytic tumors using image-based cell analysis system. 1127 8

It has been reported that microsatellite instability (MSI) strongly correlates with carcinogenesis and cancer progression. In the present study, we studied the incidence of MSI at 5 polymorphic microsatellite markers (D5S406, D13S153, D16S402, D17S796, and poly(A) tract BAT26), the expression of G1 cyclins (cyclin A, cyclin D and cyclin E), and Ki-67 labeling index in 30 surgically resected hepatocellular carcinomas (HCCs) and their adjacent non-cancerous tissues. The results of analysis showed that 43% of HCCs exhibited MSI in one locus, 10% in two loci, and 3% in three loci. Overexpressions of cyclin E and cyclin A were observed in 57% and 83% of HCCs, respectively. MSI in HCCs, however, correlated with normal expressions of cyclin E and cyclin A and with a low labeling index of Ki-67. Thus, patients with HCCs exhibiting MSI at these 5 markers may have less involvement of G1/S disregulation and may have better prognosis than other patients with HCC.
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PMID:Microsatellite instability correlates with normal expression of cyclin E in hepatocellular carcinomas. 1135 Dec 61


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