Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

It has been demonstrated that infection of primary human cells with adeno-associated viruses (AAV) leads to a decrease in cellular proliferation and to growth arrest. We analyzed the molecular basis of this phenomenon and observed that infection with AAV type 2 (AAV2) had an effect on several factors engaged in the control of the mammalian cell cycle. In particular, all of the pRB family members, pRB, p107, and p130, which are involved in G1 cell cycle checkpoint control, were affected. After infection, a shift from hyper- to hypophosphorylated forms was observed. Cyclins A and B1, which are required for G1/S transition and progression into mitosis, respectively, were downregulated at the transcriptional level as well as at the protein level, whereas the G1 cyclins D1 and E remained unaffected. In addition, the steady-state levels of cyclin-dependent kinases CDK1 and CDK2 and of transcription factor E2F-1 were diminished. Of all the factors known to be involved in phosphorylation of pRB family proteins, only the CDK inhibitor p21WAF1 exhibited a response to AAV2 infection. p21WAF1 mRNA was quickly and progressively upregulated in a p53-independent manner over at least 72 h. Consistent with the increased p21WAF1 protein levels, cyclin E- and cyclin A-dependent kinase activities declined to low levels and E2F-p130-cyclin-CDK2 complexes were disrupted. From these data, we conclude that the major effect of AAV2 infection on primary human fibroblasts appears to be upregulation of p21WAF1 gene expression and thus cell cycle arrest by the suppression of pRB family protein phosphorylation.
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PMID:Infection of primary cells by adeno-associated virus type 2 results in a modulation of cell cycle-regulating proteins. 922 93

Cdc25A, a phosphatase essential for G1-S transition, associates with, dephosphorylates, and activates the cell cycle kinase cyclin E-cdk2. p21CIP1 and p27 are cyclin-dependent kinase (cdk) inhibitors induced by growth-suppressive signals such as p53 and transforming growth factor beta (TGF-beta). We have identified a cyclin binding motif near the N terminus of Cdc25A that is similar to the cyclin binding Cy (or RR LFG) motif of the p21CIP1 family of cdk inhibitors and separate from the catalytic domain. Mutations in this motif disrupt the association of Cdc25A with cyclin E- or cyclin A-cdk2 in vitro and in vivo and selectively interfere with the dephosphorylation of cyclin E-cdk2. A peptide based on the Cy motif of p21 competitively disrupts the association of Cdc25A with cyclin-cdks and inhibits the dephosphorylation of the kinase. p21 inhibits Cdc25A-cyclin-cdk2 association and the dephosphorylation of cdk2. Conversely, Cdc25A, which is itself an oncogene up-regulated by the Myc oncogene, associates with cyclin-cdk and protects it from inhibition by p21. Cdc25A also protects DNA replication in Xenopus egg extracts from inhibition by p21. These results describe a mechanism by which the Myc- or Cdc25A-induced oncogenic and p53- or TGF-beta-induced growth-suppressive pathways counterbalance each other by competing for cyclin-cdks.
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PMID:p21CIP1 and Cdc25A: competition between an inhibitor and an activator of cyclin-dependent kinases. 923 91

Leukemia inhibitory factor (LIF) affects the growth of carcinoma cells, and we thus analyzed its underlying mechanisms. Carcinoma cells constitutively express LIF mRNA, and 23 lines (92.0%) and all (100%) of 25 lines express LIF receptor mRNAs of LIFRbeta and gp130, respectively. Exogenous addition of LIF promoted significant cell proliferation in 4 lines (MCF-7, ZR-75-1, Hs-700T and Panc-1) and suppressed cell growth in 3 lines (AZ-521, GBK-1 and HT-29). LIF significantly induced an immediate early response of genes c-fos and junB 3 hr after stimulation, but not of c-jun during the process of proliferation of MCF-7 and Hs-700T cells, with maximum levels at 30-60 min. The cell-cycle-related gene cyclin E was also induced in MCF-7 and Hs-700T cells, whereas cyclinA, cdk2, c-myc, c-myb and p53 mRNAs were not induced. On the other hand, LIF inhibited growth and increased the rate of cell death of AZ-521 and GBK-1 cells. LIF increased the number of TUNEL-positive cells in AZ-521 cells and DNA fragmentation in AZ-521 and GBK-1 cells. LIF induced apoptosis related genes c-myc and ICE during suppression of cell growth, but p53, p21, c-fos, cyclin A and cyclin E were not induced. Our results suggest that LIF is linked to cell proliferation and apoptosis in some human carcinoma cell lines. It is considered that this is related to differences in signal transduction and induction of oncogenes.
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PMID:Leukemia inhibitory factor induces apoptosis and proliferation of human carcinoma cells through different oncogene pathways. 925 11

We examined the expression of p53, p21, cyclin D1, E, and PCNA in 75 cases of gastric cancer by immunohistochemical study and the expression of p21 RNA in cases by in situ hybridization. The rate of stage III, IV cases of p53(+) p21(-) group was significantly higher than that of any other groups. The apportinately 3-year survival rate of p53(+) p21(-) group was significantly lower than either that of p21(+) p53(-) or p53(-) p21(-) group. The 3-year survival rates of positive cases were significantly lower than those of negative cases on both cyclin D1 and E. The positive rate of cyclin E of the p53(-) p21(+) group was significantly lower than that of the p53(+) p21(-) group. The average PCNA Labeling. Index (LI) of the p53(+) p21(-) group was significantly higher than that of the p53(-) p21(+) group. The 3-year survival rate of cases with expression of p21 RNA was higher than that of cases without p21 RNA. Average PCNA L1 of cases with expression of mutant-type p53 was high and the number of poor prognostic cases in cases with expression of mutant-type p53 was large. In contrast, the average PCNA LI of cases with expression of p21 was low and the number of good prognostic cases with expression of p21 was large. These results suggest that p21 suppresses synthesis of DNA via cyclin E and PCNA.
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PMID:[The significance of p21 expression in gastric cancer]. 926 17

The Raf family of protein kinases display differences in their abilities to promote the entry of quiescent NIH 3T3 cells into the S phase of the cell cycle. Although conditional activation of deltaA-Raf:ER promoted cell cycle progression, activation of deltaRaf-1:ER and deltaB-Raf:ER elicited a G1 arrest that was not overcome by exogenously added growth factors. Activation of all three deltaRaf:ER kinases led to elevated expression of cyclin D1 and cyclin E and reduced expression of p27Kip1. However, activation of deltaB-Raf:ER and deltaRaf-1:ER induced the expression of p21Cip1, whereas activation of deltaA-Raf:ER did not. A catalytically potentiated form of deltaA-Raf:ER, generated by point mutation, strongly induced p21Cip1 expression and elicited cell cycle arrest similarly to deltaB-Raf:ER and deltaRaf-1:ER. These data suggested that the strength and duration of signaling by Raf kinases might influence the biological outcome of activation of this pathway. By titration of deltaB-Raf:ER activity we demonstrated that low levels of Raf activity led to activation of cyclin D1-cdk4 and cyclin E-cdk2 complexes and to cell cycle progression whereas higher Raf activity elicited cell cycle arrest correlating with p21Cip1 induction and inhibition of cyclin-cdk activity. Using green fluorescent protein-tagged forms of deltaRaf-1:ER in primary mouse embryo fibroblasts (MEFs) we demonstrated that p21Cip1 was induced by Raf in a p53-independent manner, leading to cell cycle arrest. By contrast, activation of Raf in p21Cip1(-/-) MEFs led to a robust mitogenic response that was similar to that observed in response to platelet-derived growth factor. These data indicate that, depending on the level of kinase activity, Raf can elicit either cell cycle progression or cell cycle arrest in mouse fibroblasts. The ability of Raf to elicit cell cycle arrest is strongly associated with its ability to induce the expression of the cyclin-dependent kinase inhibitor p21Cip1 in a manner that bears analogy to alpha-factor arrest in Saccharomyces cerevisiae. These data are consistent with a role for Raf kinases in both proliferation and differentiation of mammalian cells.
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PMID:Raf-induced proliferation or cell cycle arrest is determined by the level of Raf activity with arrest mediated by p21Cip1. 927 35

We investigated the time-dependent effects of 8 Gy of gamma radiation on the activities of cyclin-dependent kinases (Cdk's) and the incorporation of the thymidine analog bromodeoxyuridine (BrdU) throughout the S phase in Chinese hamster ovary (CHO) cells. The in vitro Cdk activities of immunoprecipitated cyclin E, cyclin A and Cdk2 were reduced about 30% per cell within 0.5-1 h after irradiation, but they recovered at different rates. The kinase activity of the cyclin E-Cdk2 complex recovered first and exceeded the control values by 1.5-2 h after irradiation. Cyclin A-Cdk activities began to recover at 3-4 h after irradiation, and cyclin E/A-Cdk2 activities recovered at intermediate rates. The super-recovery of cyclin E-Cdk2 coincided with the appearance of a small synchronous population of cells entering into S phase, consistent with transient G1-phase delay/recovery regulated by cyclin E-Cdk2, whereas the activities of cyclin A-Cdk's (75% cyclin A-Cdk2; 25% cyclin A-Cdc2 when inhibition was maximal) were correlated with rates of total DNA synthesis. Multivariate flow cytometry analyses of BrdU incorporation demonstrated that radiation-induced inhibition of DNA synthesis occurred predominantly within the last quarter of S phase and that the majority of the irradiated cells failed to enter G2 phase for 4-5 h. The recovery of cyclin A-Cdk activities coincided with increased levels of total DNA synthesis and BrdU incorporation into cells within the last quarter of S phase. Western blot analysis demonstrated that levels of Waf1/p21 did not increase during inhibition of cyclin A-Cdk's and DNA synthesis in the irradiated p53-mutated CHO cells; however, Cdc2 and Cdk2 exhibited increased levels of phosphotyrosine. The results (1) indicate that the transient G1-phase delay or G1/S-phase checkpoint (Lee et al., Proc. Natl. Acad. Sci. USA 94, 526-531, 1997) is mediated by inhibition of cyclin E-Cdk2 and (2) point to the existence of a radiation-induced S-phase checkpoint located about 75% into S phase involving the inhibition of cyclin A-Cdk's by a p53/Waf1-independent pathway in CHO cells.
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PMID:Association of G1/S-phase and late S-phase checkpoints with regulation of cyclin-dependent kinases in Chinese hamster ovary cells. 929 58

Recently we have shown that in fibroblasts (NIH 3T3 and Rat-1 cells) inhibition of protein geranylgeranylation leads to a G0/G1 arrest, whereas inhibition of protein farnesylation does not affect cell cycle distribution. Here we demonstrate that in human tumor cells the geranylgeranyltransferase-I (GGTase-I) inhibitor GGTI-298 blocked cells in G0/G1, whereas the farnesyltransferase (FTase) inhibitor FTI-277 showed a differential effect depending on the cell line. FTI-277 accumulated Calu-1 and A-549 lung carcinoma and Colo 357 pancreatic carcinoma cells in G2/M, T-24 bladder carcinoma, and HT-1080 fibrosarcoma cells in G0/G1, but had no effect on cell cycle distribution of pancreatic (Panc-1), breast (SKBr 3 and MDAMB-231), and head and neck (A-253) carcinoma cells. Furthermore, treatment of Calu-1, Panc-1, Colo 357, T-24, A-253, SKBr 3, and MDAMB-231 cells with GGTI-298, but not FTI-277, induced the protein expression levels of the cyclin-dependent kinase inhibitor p21WAF. HT-1080 and A-549 cells had a high basal level of p21WAF, and GGTI-298 did not further increase these levels. Furthermore, GGTI-298 also induces the accumulation of large amounts of p21WAF mRNA in Calu-1 cells, a cell line that lacks the tumor suppressor gene p53. There was little effect of GGTI-298 on the cellular levels of another cyclin- dependent kinase inhibitor p27KIP as well as cyclin E and cyclin D1. These results demonstrate that GGTase-I inhibitors arrest cells in G0/G1 and induce accumulation of p21WAF in a p53-independent manner and that FTase inhibitors can interfere with cell cycle events by a mechanism that involves neither p21WAF nor p27KIP. The results also point to the potential of GGTase-I inhibitors as agents capable of restoring growth arrest in cells lacking functional p53.
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PMID:The geranylgeranyltransferase-I inhibitor GGTI-298 arrests human tumor cells in G0/G1 and induces p21(WAF1/CIP1/SDI1) in a p53-independent manner. 934 Nov 67

Overexpression of cyclin D1 has been implicated in the malignant transformation of a variety of human cancers, including urinary bladder carcinomas. However, few reports have addressed the significance of cyclin D1 overexpression in chemical carcinogenesis in rodents. In the present study, we evaluated the oncogenic potential of cyclin D1 in experimental rat urinary bladder carcinogenesis and its relationships to the oncogenes cyclin E, K-ras, and H-ras as well as tumor suppressor genes p53 and p21WAF1/Cip1. In addition, proliferation status of preneoplastic lesions and tumors was assessed by proliferating cell nuclear antigen immunohistochemistry. Fisher 344 rats were initiated with 0.05% N-butyl-N-(4-hydroxybutyl)nitrosamine in the drinking water for 4 weeks and then administered 5% sodium L-ascorbate in diet. Animals were sacrificed at weeks 4, 8, 12, 18, and 24. Preneoplastic lesions such as papillary or nodular hyperplasia and neoplastic lesions of the urinary bladder were observed during carcinogenesis. By immunohistochemical examination, overexpression of cyclin D1 protein was observed in 17% of papillary or nodular hyperplasias, 66% of papillomas, and 69% of transitional cell carcinomas, whereas nuclear accumulation of p53 was observed in none of the preneoplastic lesions and in fewer than 2% of transitional cell carcinomas. Overexpression of cyclin D1 in preneoplastic lesions and tumors was not dependent on the size of the tumors or their proliferation status. Quantitation of mRNA in tumors by multiplex reverse transcription-PCR showed that average mRNA expression of cyclin D1 and cyclin E was increased, whereas average p21WAF1/Cip1 mRNA expression was decreased. More than 2-fold overexpression of cyclin D1 mRNA was observed in 50 and 60% of tumors at weeks 18 and 24, respectively. Localization of cyclin D1 mRNA expression was demonstrated by in situ hybridization, and the results were comparable to immunohistochemistry findings. None of the 25 tumors we examined by PCR-single-strand conformational polymorphism analysis harbored p53 mutations, H-ras mutations, or K-ras mutations. Thus, during the promotion phase of two-stage bladder carcinogenesis, overexpression of cyclin D1 in tumor cells may provide yet another mechanism by which tumors can gain a growth advantage. In contrast, tumors with mutated p53 may not have a growth advantage. Our results suggest that overexpression of cyclin D1 plays a critical role during urinary bladder carcinogenesis.
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PMID:Cyclin D1 overexpression in rat two-stage bladder carcinogenesis and its relationship with oncogenes, tumor suppressor genes, and cell proliferation. 935 38

Cyclin E is a G1 cyclin that is essential for the transition from G1 to S phase in the cell cycle. Alterations to cyclin E expression or regulation could be important in tumorigenesis. Previous immunohistochemical and immunoblotting studies have investigated the expression of cyclin E in breast carcinomas. In this study, cyclin E has been investigated in a range of non-malignant and malignant breast using immunohistochemistry. Normal and benign tissue from pre- and post-menopausal women (39 cases), non-involved tissue from cancer-containing breasts (47 cases), ductal carcinoma in situ (22 cases) and invasive breast carcinomas (109 cases) have been examined. There was no reactivity in any of the non-malignant breast. Only one ductal carcinoma in situ contained more than 5% reactive cells. A total of 28% of invasive carcinomas had > 5% of reactive cells (range 0-88% positive cells, mean 12.59%, median 1.0%). A significant association was found with poorer differentiation (P < 0.001), high MIB1 index (P < 0.001), lack of oestrogen receptor (0.05 > P > 0.025) and the presence of p53 protein (0.05 > P > 0.025). Virtually all cases with cyclin E and p53 were poorly differentiated. The presence of cyclin E is therefore only found in breast malignancies and is associated with more aggressive features, including high proliferation.
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PMID:Lack of cyclin E immunoreactivity in non-malignant breast and association with proliferation in breast cancer. 937 73

Cell cycle perturbations in three lung carcinoma cell lines (U-1285,U1906 and U-1810) with different intrinsic radiosensitivities (SF2 U-1285 = 0.25, SF2 U-1906 = 0.45, SF2 U-1810 = 0.88) were investigated following x-irradiation. Cell cycle flow calculations showed that the G1-->S-phase transit was accelerated in irradiated compared with untreated U-1285 cells, up to 24 hours postirradiation. In U-1810 cells and U-1906 cells the postirradiation G1-->S transit decreased compared with controls. All three cell lines showed no postirradiation induction of p53 and p21CIP1 proteins. Cyclin E was overexpressed and cyclin E-dependent kinase activity was substantially induced by irradiation in U-1285 cells compared with U-1906 and U1810 cells while p27KIP1 was detected at the highest intensity in U-1810 cells and lowest in U-1285 cells. We hypothesise that the accelerated postirradiation G1-->S transit in U-1285 cells is associated with induction of cyclin E-dependent kinase activity and may account for increased radiosensitivity in these cells.
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PMID:Characterisation of the G1/S cell cycle checkpoint defect in lung carcinoma cells with different intrinsic radiosensitivities. 941 76


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