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)

The myelodysplastic syndromes (MDS) are clonal myeloid disorders characterized by bone marrow cell dysplasia and ineffective hematopoiesis leading to peripheral refractory cytopenias. The course of the disease ranges from a chronic status with progressively impaired hematopoiesis to rapid evolution to acute myeloid leukemia (AML). A panel of continuous malignant hematopoietic cell lines has been established from the whole spectrum of MDS variants and also from the different stages of the diseases, namely from the MDS phase or the overt leukemia post-MDS phase. Ten cell lines were derived from the various MDS subtypes; 17 cell lines were established from patients with leukemia (mainly AML) post-MDS. While most cell lines display myelocytic, monocytic or erythroid features, some cell lines carry lymphoid characteristics (precursor B-cell, B-cell, or T-cell), With regard to these lymphoid MDS-derived cell lines, more detailed authentication (prove of derivation from the assumed patient) and verification (prove of the malignant nature of the cell line and derivation from the assumed neoplastic cells) are required to validate the cell lines as true in vitro representatives of MDS and to exclude any cross-contamination with other cells or immortalization of normal bystander cells. On the other hand, lymphoid MDS-derived cell lines may attest to the clonal nature of MDS which may afflict progenitor cells giving rise to lymphoid or myelomonocytoid cells. Many of the MDS-derived cell lines carry cytogenetic and molecular genetic abnormalities typically associated with MDS: gain or loss of all or parts of chromosomes 5, 7, 8 and 20 (-5/5q-, -7/7q-, + 8, 20q-); alterations of oncogenes and tumor suppressor genes (IRF-1, p15, p16, p53, RAS, RB). In summary, the present panel of cell lines provides continuously growing cells and thus unlimited cell material for use as in vitro paradigms covering the whole spectrum of MDS-related hematopoetic malignancies. Properly authenticated and verified MDS-derived cell lines which should be made freely available will represent important research tools for the study of MDS biology.
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PMID:Malignant hematopoietic cell lines: in vitro models for the study of myelodysplastic syndromes. 1065 45

Genetic aberrations associated with the development of extranodal high-grade large B-cell lymphoma originating in the stomach have not been fully identified yet. We analyzed 31 such lymphomas using 73 microsatellite markers for allelic imbalance and microsatellite instability. The highest frequency (42%) of loss of heterozygosity (LOH) was found on the long arm of chromosome 6. We identified 2 LOH hot spots on 6q21-22.1 and 6q23.3-25, flanked by markers D6S246-D6S261 and D6S310-D6S441, respectively, containing putative tumor suppressor genes (TSGs). These 6q aberrations were found to be the sole allelic imbalance in 1 patient only; they were mostly accompanied by additional abnormalities. Several known TSGs, namely, the APC, p15/p16, p53, and DCC genes, were found to suffer frequent LOH during lymphomagenesis. LOH was also detected in regions containing putative TSGs on 7q and 13q14. Frequent amplification of genomic material was found in the 2p, 3q27 at the BCL-6 gene locus, 6p, 7q, 11q23-24 at the MLL gene locus, and 18q regions. Analysis of the pattern of occurrence of these aberrations revealed an association of the amplification of the MLL gene region with LOH at the p53 locus (P =.02). Only low frequency of microsatellite instability (MSI) was detected in these lymphomas and MSI incidence increased with age (P =.01). Karyotypic instability thus plays the main role in the development of gastric high-grade large B-cell lymphoma. Common genetic aberrations responsible for lymphomagenesis are deletions of 6q, loss of p53, and amplification of the 3q27 and the MLL gene regions. (Blood. 2000;95:1180-1187)
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PMID:Genetic aberrations common in gastric high-grade large B-cell lymphoma. 1066 88

Elevation of the cyclin-dependent kinase (cdk) inhibitor, p27(kip1) is necessary for Interleukin (IL)-4-mediated growth arrest of human low grade astrocytoma (RTLGA) cells and occurs at 24 h of treatment. Pathways involved in IL4 alteration of p27(kip1) are unknown, however. Here we investigated whether other cdk inhibitors contributed to the actions of IL-4 on RTLGA cells. By 12 h of IL-4 treatment, both cdk4 and cdk2 kinase activities against the retinoblastoma protein (pRb) were reduced and nuclear entry of pRb was prohibited. Twelve-hour cdk complexes contained elevated p21(waf1/cip1) but not p27(kip1), p15(ink4B) or p16(ink4A). IL-4 increased p21(waf1/cip1) but not p27(kip1) mRNA levels, and stimulated luciferase activity of a p21(waf1/cip1) promoter-luciferase reporter. In p53-mutant WITG3 cells, IL-4 did not alter p21(waf1/cip1) mRNA and promoter-luciferase activity or p27(kipl) protein, suggesting a need for functional p53. STAT6 phosphorylation by IL-4, however, occurred in both p53-mutant WITG3 and p53-functional RTLGA cells. Pre-treatment of RTLGA with anti-sense but not missense p21(waf1/cip1) oligonucleotide prior to IL-4: (a) restored cdk activities; (b) reduced cdk4-associated p21(waf1/cip1) levels; (c) prevented p27(kipl) elevation; and (d) reversed growth arrest. These results are the first to suggest that p21(waf1/cip1) is essential for IL-4-mediated elevation of p27(kip) and growth arrest of astrocytoma cells.
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PMID:Anti-sense oligonucleotide of p21(waf1/cip1) prevents interleukin 4-mediated elevation of p27(kip1) in low grade astrocytoma cells. 1069 11

The INK4a/ARF locus encodes two different proteins involved in cell cycle control. Both molecules, p16(INK4a) and p19(ARF), inhibit cell cycle progression and have been shown to act as tumor suppressors in a variety of models. Their expression is controlled by separate promoters responding to different stimuli and they therefore show independent transcriptional regulation. We have cloned and characterized a 2.5 kb region upstream of the murine p19(ARF) gene to determine the role of DNA methylation in suppressing p19(ARF) transcription in a wide panel of murine primary T cell lymphomas. This region contains a DNA fragment with the characteristics of a CpG island similar to those described for the murine p16(INK4a) and p15(INK4b) genes. Expression of p19(ARF) is decreased in a significant number (20%) of the murine lymphomas analyzed. Overexpression of the p19(ARF) transcript is also frequent, suggesting alterations in molecules of the retinoblastoma or p53 pathways that are involved in p19(ARF) regulation. Although hypermethylation of the INK4a and INK4b promoters is frequently involved in murine lymphomas, the p19(ARF) CpG island is infrequently methylated in the murine primary lymphomas studied in this work. Since loss of p19(ARF) expression cannot be explained as the result of homozygous deletions or hypermethylation of the ARF gene, other regulatory mechanisms seem to be altered in these malignancies.
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PMID:Characterization of the murine p19(ARF) promoter CpG island and its methylation pattern in primary lymphomas. 1075 21

A senescence-like growth arrest is induced in mouse primary embryo fibroblasts by inhibitors of phosphoinositide 3-kinase (PI3K). We observed that senescence-like growth arrest is correlated with an increase in p27(Kip1) but that down-regulation of other cyclin-dependent kinase (CDK) inhibitors, including p15(INK4b), p16(INK4a), p19( INK4d), and p21(Cip1) as well as other negative cell cycle regulators such as p53 and p19(ARF), implies that this senescence-related growth arrest is independent of the activity of p53, p19(ARF), p16(INK4a), and p21(Cip1), which are associated with replicative senescence. The p27(Kip1) binds to the cyclin/CDK2 complexes and causes a decrease in CDK2 kinase activity. We demonstrated that ectopic expression of p27(Kip1) can induce permanent cell cycle arrest and a senescence-like phenotype in wild-type mouse embryo fibroblasts. We also obtained results suggesting that the kinase inhibitors LY294002 and Wortmannin arrest cell growth and induce a senescence-like phenotype, at least partially, through inhibition of PI3K and protein kinase B/Akt, activation of the forkhead protein AFX, and up-regulation of p27(Kip1)expression. In summary, these observations taken together suggest that p27(Kip1) is an important mediator of the permanent cell cycle arrest induced by PI3K inhibitors. Our data suggest that repression of CDK2 activity by p27(Kip1) is required for the PI3K-induced senescence, yet mouse embryo fibroblasts derived from p27(Kip1-/-) mice entered cell cycle arrest after treatment with LY294002. We show that this is due to a compensatory mechanism by which p130 functionally substitutes for the loss of p27(Kip1). This is the first description that p130 may have a role in inhibiting CDK activity during senescence.
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PMID:Inhibition of the phosphoinositide 3-kinase pathway induces a senescence-like arrest mediated by p27Kip1. 1079 51

We have analyzed the expression of the CDKN1A (p21(CIP1)), CDKN1B (p27(Kip1)), TP53, RB1 and MDM2 proteins and tumor cell proliferation by immunohistochemical staining in 59 cases of metastatic melanoma. The genomic status of the CDKN2A (INK4-ARF, p16/p14(ARF)), CDKN2B (p15) and CDKN2C (p18) genes was determined by PCR-SSCP (single-strand conformation polymorphism) in 46 of these cases. These results were correlated with various clinico-pathological parameters, including the outcome of combined chemoimmunotherapy. We found positive correlations between the expression of CDKN1A and MDM2 (r = 0.5063, P = 0.001), between the expression of CDKN1B and RB1 (r = 0.5026, P = 0.001), and between RB1 expression and tumor cell proliferation (0.5564, P<0.001). Two mutations in the CDKN2A (p16) gene were detected, including a novel base change AAC-->ATC (Asn to Ile) at codon 71, that also changes the codon 85 of the alternative reading frame gene p14(ARF) from CAA to CAT (Gln to His). Homozygous deletion at exon 2 of the CDKN2A (INK4-ARF) gene was detected in six cases. In seven cases, the 540C-->G polymorphism in the 3'UTR of the CDKN2A (p16) gene was found in linkage disequilibrium with the 74C-->A polymorphism in intron 1 of the CDKN2B gene (P < 0.0001). These cases had significantly lower expression of the TP53 protein (P = 0.0032). Both 540C-->G and 580C-->T polymorphisms in the 3'UTR of the CDKN2A (p16) gene were associated with significantly shorter progression time from primary to metastatic disease (P = 0.0071). We conclude, that although none of the analyzed cell cycle regulators could be singled out as a major prognostic factor, G(1)/S checkpoint abnormalities remain one of the most significant factors in the development of malignant melanoma.
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PMID:Analysis of G(1)/S checkpoint regulators in metastatic melanoma. 1086 49

Cyclin-dependent kinase inhibitors (CKIs) prevent cyclin-dependent kinases from phosphorylating critical substrates such as retinoblastoma gene protein (pRb), hence blocking the cascade of events leading to cell proliferation. Currently, the list of CKIs includes p21WAF1/Cip1, p27Kip1, p57Kip2 (the Cip/Kip family), p15/ INK4b, p16/INK4a, p18/INK4c, and p19/INK4d (the INK4 family). Among them, p27 plays a crucial role linking extracellular growth-regulatory signals to progression to or exit from the cell cycle. Unlike p53, p16, and Rb, mutations in Kip1 and WAF1 genes are distinctly rare in bladder cancer. We analyzed immunohistochemically the expression of p27 and other interacting G1 proteins (ie, p21, p16, pRb, p53) in 120 consecutive cases of transitional cell carcinomas (TCCs) and related it to proliferation rate, clinicopathologic parameters, and survival. p27 levels were significantly higher in low-grade (P = .001), superficial (Ta-T1) (P = .001), papillary (P < .001), and slowly proliferating TCCs (rs = -0.235, P = .05). p27 also positively correlated with p16 expression (rs = 0.212, P = .05). In univariate analysis, decreased p27 expression was associated with poor overall (P = .0109) and postrelapse (P = .0344) survival, especially if combined to increased Ki-67 expression (P = .0004 and P = .036, respectively). Furthermore, in multivariate analysis, Ki-67/p27 status had the strongest bearing on the overall survival of muscle-invasive TCCs (P = .0019). Our results indicate that low p27 expression is more common in poorly differentiated muscle-invasive TCCs and is a major player in cell cycle control in these neoplasms. More importantly, the combined Ki-67/p27 expression provides prognostic information beyond that provided by conventional parameters or other cell cycle-related proteins, concerning overall survival in muscle-invasive TCCs.
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PMID:Cell cycle regulators in bladder cancer: a multivariate survival study with emphasis on p27Kip1. 1087 71

Hereditary cancer syndrome is mainly caused by tumor suppressor genes, such as p53 gene in Li-Fraumeni syndrome and p16 gene in familial melanoma. There are 2 signal pathways of regulation of cell cycle, RB pathway and p53 pathway. Cyclin dependent kinase(CDK) was regulated by CDK inhibitor(CDKI) (p16, p15), and CDK-CDKI complex control RB by phosphorylation. p53 regulate RB pathway through p21. p53 is involved in apoptosis through bcl 2 or Bax 3. p19 coded by exon 1 beta and exons 2 and 3 of p16 gene, binds to MDM2 and regulate p53 pathway. Chromosome 9p21 locus, which p16, p15 and p19 genes are assigned, is important to regulate both RB and p53 pathways.
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PMID:[Mechanism of tumorigenesis caused by tumor suppressor gene]. 1087 46

We have previously identified activation of ras proto-oncogenes and inactivation of tumor suppressor genes including p53, p16(INK4a) and p15(INK4b) in 2',3'-dideoxycytidine (ddC)- and/or 1,3-butadiene (BD)-induced lymphomas derived from B6C3F1 (C57BL/6xC3H/He) mice, indicating that alterations of ras signaling pathway, p53 and pRb growth control pathways are important in the development of these chemically induced lymphomas. However, there is still a subset of tumors that displayed no changes in these genes. Thus, we investigated whether the Raf1, Mdm2, c-Myc, Cdc25a and Cdc25b proto-oncogenes, which are implicated in the ras or p53 or pRb pathways, are alternative oncogenic target genes. Analyses of gross genomic alterations by Southern blots failed to reveal rearrangement or amplification in any of the tumors examined. Frequent point mutations on the substrate binding domain of the Raf1 gene has been reported in 1-ethyl-1-nitrosourea (ENU)-induced murine lymphomas and lung tumors, along with a conspicuous lack of ras mutations [U. Naumann, I. Eisenmann-Tappe, U.R. Rapp, The role of raf kinases in development and growth of tumors, Recent Results Cancer Res., 143 (1997) 237-244]. To investigate whether Raf1 mutation is involved in our set of tumor especially those without ras mutations, the PCR-based single-strand conformation analyses (SSCA) and direct DNA sequencing were employed. No mutations but four genetic polymorphisms between C57BL/6 and C3H/He were found, with two of them reported as point mutations previously (op. cit.). The polymorphisms were utilized for allelic loss study of Raf1 locus. Losses of heterozygosity were found in six of 31 BD-induced lymphomas. These results indicate that genetic alterations of c-Myc, Cdc25, Raf1 and Mdm2 proto-oncogenes may not be involved in the development of ddC- and BD-induced lymphomas and the inactivation of tumor suppressor gene(s) located close to Raf1 gene might be important in the development of a subset of BD-induced lymphomas.
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PMID:Genetic analysis of Raf1, Mdm2, c-Myc, Cdc25a and Cdc25b proto-oncogenes in 2',3'-dideoxycytidine- and 1,3-butadiene-induced lymphomas in B6C3F1 mice. 1089 86

Retinoids are promising agents for the prevention and treatment of several human malignancies including lung cancer. In this study, the effect of retinoic acid (RA) on cell growth and the mechanism of growth modulation were examined in human lung squamous carcinoma CH27 cells. Here we report that RA mediated the dose- and time-dependent growth arrest in G1 phase, accompanied by the up-regulation of p27(Kip1) and the down-regulation of the cyclin-dependent kinase 3 (Cdk3) and p21(CIP1/Waf1) proteins. Furthermore, RA-induced growth arrest of CH27 cells was also associated with increased retinoic acid receptor beta (RARbeta) and reduced c-Myc expression. However, RA had no effect on the levels of cyclins A, D1, D3, E, or H, or on Cdk2, Cdk4, Cdk5, CDk6, Cdk7, p16(Ink4A), p15(Ink4B), p53, or pRb proteins in CH27 cells. Evaluation of the kinase activity of cyclin-Cdk complexes showed that RA increases p27(Kip1) expression in CH27 cells leading to markedly reduced cyclin A/Cdk2 kinase activity and slightly reduced cyclin E/Cdk2 kinase activity, with no effect on cyclin D/Cdk4 and cyclin D/Cdk6 activities. Moreover, coincident with the decrease in kinase activity was a drastic increase in cyclin A-bound p27(Kip1). These results suggest that increases in the levels of p27(Kip1) and its binding to cyclin A, as well as reduction of Cdk3 protein expression, are strong candidates for the cell cycle regulator that prevents the entry into the S phase in RA-treated CH27 cells, with prolongation of G1 phase and inhibition of DNA synthesis.
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PMID:Retinoic acid-mediated G1 arrest is associated with induction of p27(Kip1) and inhibition of cyclin-dependent kinase 3 in human lung squamous carcinoma CH27 cells. 1089 83


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