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)

We have previously found that bone morphogenetic protein-2 (BMP-2), a member of the transforming growth factor-beta family, induces cell-cycle arrest in the G1 phase and apoptotic cell death of HS-72 mouse hybridoma cells. In this study, we show that BMP-2 did not alter expression of cyclin D, cyclin E, cyclin-dependent kinase 2 (CDK2), CDK4, p27KIP1, p16INK4a, or p15INK4b, but enhanced expression of p21(CIP1/WAF1). Accumulation of p21(CIP1/WAF1) resulted in increased binding of p21(CIP1/WAF1) to CDK4 and concomitantly caused a profound decrease in the in vitro retinoblastoma protein (Rb) kinase activity of CDK4. Furthermore, the ectopic expression of human papilloma virus type-16 E7, an inhibitor of p21(CIP1/WAF1) and Rb, reverted G1 arrest induced by BMP-2. Expression of E6/E7, without increasing the p53 level, blocked inhibition of Rb phosphorylation and G1 arrest, but did not attenuate cell death in BMP-treated HS-72 cells. Taken together, these results suggest that inhibition of Rb phosphorylation by p21(CIP1/WAF1) is responsible for BMP-2-mediated G1 arrest and that BMP-2-induction of apoptosis might be independent of Rb hypophosphorylation.
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PMID:Dissociation of bone morphogenetic protein-mediated growth arrest and apoptosis of mouse B cells by HPV-16 E6/E7. 1085 68

The transcription factor E2F-1 has been postulated to play a crucial role in the control of cell cycle progression because of its ability to be bound and regulated by the retinoblastoma gene product (pRb). Exogenous expression of E2F-1, under growth restrictive conditions, was shown to result in p53-dependent programmed cell death. The consequences of deregulated expression of E2F-1 on terminal differentiation of hematopoietic cells in the absence of E2F-1-mediated apoptosis, as well as mechanistic insights into how deregulated E2F-1 may affect terminal differentiation, have not been established. The autonomously proliferating M1 myeloblastic leukemia cell line, which is null for p53 expression and can be induced by interleukin-6 (IL-6) to undergo terminal macrophage differentiation with concomitant loss of leukemogenicity, provides a particularly attractive model system to address these issues. Deregulated and continued expression of E2F-1 blocked the IL-6-induced terminal differentiation program at an early blast stage, giving rise to immature cells, which continued to proliferate without undergoing apoptosis and retained their leukemogenic phenotype. Although E2F-1 blocked IL-6-mediated terminal differentiation and its associated growth arrest, it did not prevent the rapid induction of both p15(INK4B) and p16(INK4A), inhibition of cdk4 kinase activity, and subsequent hypophosphorylation of pRb. The results obtained imply that genetic alterations that both impair p53 function and deregulate E2F-1 expression may render hematopoietic cells refractory to the induction of differentiation and are, thereby, likely to play a major role in the progression of leukemias. (Blood. 2000;96:475-482)
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PMID:Deregulated E2F-1 blocks terminal differentiation and loss of leukemogenicity of M1 myeloblastic leukemia cells without abrogating induction of p15(INK4B) and p16(INK4A). 1088 8

The Ras family of small GTPases includes three closely related proteins: H-, K-, and N-Ras. Ras proteins are involved in the transduction of signals elicited by activated surface receptors, acting as key components by relaying signals downstream through diverse pathways. Mutant, constitutively activated forms of Ras proteins are frequently found in cancer. While constitutive Ras activation induces oncogenic-like transformation in immortalized fibroblasts, it causes growth arrest in primary vertebrate cells. Induction of p53 and cyclin-dependent kinase inhibitors such as p15INK4b, p16INK4a, p19ARF, and p21WAF1 accounts for this response. Interestingly, while ras has usually been regarded as a transforming oncogene, the analysis of Ras function in most of the cellular systems studied so far indicates that the promotion of differentiation is the most prominent effect of Ras. While in some cell types, particularly muscle, Ras inhibits differentiation, in others such as neuronal, adipocytic, or myeloid cells, Ras induces differentiation, in some cases accompanied by growth arrest. Several possible mechanisms for the pleiotropic effects' of Ras in animal cells are discussed.
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PMID:Ras proteins in the control of the cell cycle and cell differentiation. 1109 55

The existence of genetic alterations affecting genes involved in cellular proliferation and death, such as TP53 and K-ras, is one of the most common features of tumour cells. Recently, gene inactivation by promoter hypermethylation has been demonstrated. Methylation is the main epigenetic modification in mammals and abnormal methylation of the CpG islands located in the promoter region of the genes leads to transcriptional silencing. Examples include the p16INK4a, p15INK4B, p14ARF, Von Hippel-Lindau (VHL), the oestrogen and progesterone receptors, E-cadherin, death associated protein (DAP) kinase and the first tumour suppressor gene described, retinoblastoma (Rb) gene. In most cases, methylation involves loss of expression, absence of a coding mutation and restoration of transcription by the use of demethylating agents. However, is there a linkage between genetic and epigenetic alterations? Our results show one side of this puzzle demonstrating that epigenetic lesions drive genetic lesions in cancer. Four specific epigenetic lesions, promoter hypermethylation of the DNA mismatch repair gene hMLH1, the DNA alkyl-repair gene O(6)-methylguanine-DNA methyltransferase (MGMT), the detoxifier glutathione S-transferase P1 (GSTP1) and the familial breast cancer gene BRCA1 may lead to four specific genetic lesions, microsatellite instability, G to A transitions, steroid-related adducts and double-strand breaks in DNA. This is probably only the beginning of an extensive list of epigenetic events that change and make the genetic environment of the transformed cell unstable.
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PMID:Epigenetic lesions causing genetic lesions in human cancer: promoter hypermethylation of DNA repair genes. 1109 2

The p16INK4 gene, which is a tumor suppressor gene, is frequently altered in lung cancers. Hypermethylation of the promoter region of the p16INK4 gene seems to be the major mechanism through which p16INK4 become inactivated. Hypermethylation of the p16INK4 gene was reported to occur at an early stage in lung cancer. To determine whether the change in p16INK4 methylation status occurs at the late stage in the progression of primary lung cancers, we analyzed the primary and metastatic tumor tissues and normal lung samples from 29 cases of advanced lung cancer with distant metastasis. In each tissue sample, we analyzed the p16INK4 and p15INK4b genes for mutations and the methylation status of both genes using PCR-single strand conformation polymorphism, direct sequencing, and methylation-specific PCR analysis. We also analyzed a subset of the samples for p16INK4 protein expression. Genetic mutations in the coding region of the p16INK4 and p15INK4b genes were not found in any of the examined specimens. The promoter region of the p16INK4 gene was hypermethylated in the tumor samples of the primary or metastatic site of 37.0% (10 of 27) of the subjects. The promoter region of the p16INK4 gene was hypermethylated at both the primary and metastatic sites in two of the 10 cases and at only the metastatic site in 8 cases. By immunohistochemical analysis, we confirmed the presence of p16INK4 protein at the primary site of all cases in which the promoter region of the p16INK4 gene was hypermethylated at only the metastatic site. Interestingly, all 8 cases with a hypermethylated p16INK4 promoter region, at only the metastatic site, did not have p53 mutation. The results of this study indicate that tumor cells in which the p16INK4 gene has been inactivated by hypermethylation of the promoter region could have an advantage in progression and metastasis in non-small cell lung cancers, especially in the tumors with normal p53, and that the frequency of p16INK4 gene inactivation by hypermethylation could vary in clinical course.
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PMID:Increase in the frequency of p16INK4 gene inactivation by hypermethylation in lung cancer during the process of metastasis and its relation to the status of p53. 1110 48

Loss of the G1 checkpoint appears to be extremely common among virtually all neoplasms. A variety of genetic and epigenetic mechanisms have been demonstrated to play significant roles in this process. In a consecutive series of early stage non-small cell lung cancer (NSCLC), we have established the loss of expression of the G1 Cdk inhibitors p15INK4b) and p16INK4a by DNA methylation is very common (37%), and methylation of p16INK4a is tightly correlated with loss of expression of p16INK4a protein (P = 0.0018). Furthermore, methylation of p15INK4b and p16INK4a appear inversely correlated, although methylation of p15INK4b is an infrequent event in this cohort (4%). Methylation was detected in all stages of NSCLC equally, and did not correlate with survival in these patients. Evidence for methylation was more frequent in squamous cell carcinomas in comparison to other tumor histologies (P = 0.0156). In addition, over-expression of cyclin D1 was found to be tightly restricted (P = 0.0032) to those tumors that had retained wild-type expression of pRB, and did not correlate with methylation or expression of p16INK4a gene product. Although loss of p16INK4a function remains tightly correlated with pRB expression, loss of other regulatory elements in NSCLC such as p53 mutation and cyclin D1 over-expression appear independent of loss of the p16INK4a gene product.
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PMID:Mechanisms of G1 checkpoint loss in resected early stage non-small cell lung cancer. 1128 26

Acute myelogenous leukemia is a heterogeneous disease that appears to evade the normal regulatory controls of tumor suppressor genes. Studies in AML have documented mutations in both p53 and Retinoblastoma (Rb) genes, but these mutations are relatively uncommon, especially compared to their mutational frequency in solid tumors. In addition, expression abnormalities have now been documented in several tumor suppressor genes or related genes including MDM2, p73, Rb, p14(ARF), p15(INK4B), and p16(INK4A). We review the current literature regarding tumor suppressor genes in AML and suggest how these genes may be involved in the development of the disease.
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PMID:Malignancy: Tumor Suppressor Gene Aberrations in Acute Myelogenous Leukemia. 1139 98

Lung cancer is a leading cause of cancer death worldwide; however, despite major advances in cancer treatment during the past two decades, the prognostic outcome of lung cancer patients has improved only minimally. This is largely due to the inadequacy of the traditional screening approach, which detects only well-established overt cancers and fails to identify precursor lesions in premalignant conditions of the bronchial tree. In recent years this situation has fundamentally changed with the identification of molecular abnormalities characteristic of premalignant changes; these concern tumour suppressor genes, loss of heterozygosity at crucial sites and activation of oncogenes. After considering the morphological modifications that occur in premalignant lesions of the bronchial tree, we analyse the alterations occurring in a series of relevant genes: p53 and its functional regulation by MDM2 and p14ARF, p16INK4, p15INK4b, FHIT, as well as LOH at important sites such as 3p, 8p, 9p and 5q. Activation of oncogenes is considered for K-ras, the cyclin D1, the heterogeneous nuclear ribonucleoprotein A2/B1 (hnRNPA2/B1), and finally the c-myc oncogene. The expression of c-myc is influenced strongly by the presence of growth factors (GFs), among which EGF is of prime importance, as well as its receptor coded for by the c-erbB-2 oncogene. Basic knowledge at the molecular level has extremely important clinical implications with regard to early diagnosis, risk assessment and prevention, and therapeutic targets. The novel techniques for early diagnosis and screening of premalignant lung lesions, such as fluorescence bronchoscopy, endobronchial ultrasound, spiral computed tomography combined with precise spatial localization techniques, should basically change the approach to the problems raised by this disease and allow for an increased discovery rate of incipient lesions. Sequential applications will lead to the identification of individuals/populations at high risk, while the availability of accurate 'intermediate end points' will enable the effects of preventive trials to be monitored. Finally, the same molecular abnormalities may serve as 'starting points' for innovative treatments designed to restore the altered functions to normality. Recent developments in our knowledge and understanding of the molecular genetic abnormalities in premalignant lung lesions open an era of hope.
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PMID:Molecular genetic abnormalities in premalignant lung lesions: biological and clinical implications. 1143 8

Medulloblastomas exhibit an array of diverse cytogenetic abnormalities. To evaluate the significance of epigenetic rather than genetic lesions in medulloblastomas and other primitive neuroectodermal tumors (PNETs) of the childhood CNS we performed a systematic analysis of gene specific and global methylation. Methylation-specific PCR detected no methylation for p15(INK4B), von Hippel Lindau and TP53 and only limited methylation for E-Cadherin and p16(INK4A) in tumors. The cell lines Daoy and MHH-PNET-5 in which the p16(INK4A) promoter was methylated did not express the gene, but demonstrated abnormalities by SSCP. Immunohistochemistry for p16 was negative in all examined normal cerebella and medulloblastomas. Using the technique of Restriction Landmark Genomic Scanning we detected methylation affecting up to 1% of all CpG islands in primary MB/PNETs and 6% in MB cell lines. Methylation patterns differed between medulloblastomas and PNETs. Examination of several methylated sequences revealed homologies to known genes and expressed sequences. Analysis of survival data identified seven of 30 hypermethylated sequences significantly correlating with poor prognosis. We suggest that DNA hypermethylation has an outstanding potential for the identification of novel tumor suppressors as well as diagnostic and therapeutic targets in MBs and other PNETs of the CNS.
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PMID:Aberrant promoter methylation of previously unidentified target genes is a common abnormality in medulloblastomas--implications for tumor biology and potential clinical utility. 1152 88

Natural killer (NK) cell neoplasms, which are derived from mature or precursor NK cells, are rare diseases and are observed predominantly in Asian countries. We analyzed the status of the Rb, p53, p15INK4B, p16INK4A and p14ARF genes in these diseases by Southern blot, polymerase chain reaction-single strand conformational polymorphism (PCR-SSCP) and western blot analysis. We used 31 NK cell neoplasms, including four cell lines derived from NK cell neoplasms, 3 myeloid / NK cell precursor acute leukemias, 4 blastic NK cell lymphoma / leukemias, 4 aggressive NK cell leukemia / lymphomas, 4 nasal NK cell lymphomas, and 12 chronic NK lymphocytosis. We found gene amplification of the p53 gene in one nasal NK cell lymphoma, and point mutations of the p53 gene in one blastic NK cell lymphoma / leukemia and one chronic NK lymphocytosis. In addition, homozygous deletions of p15, p16 and p14 genes in 5 out of 31 samples were detected; 3 were from nasal NK cell lymphoma and 2 from blastic NK cell lymphoma / leukemia. Also hemizygous deletion of the Rb gene in one blastic NK cell lymphoma was detected. Rb proteins were highly expressed in one cell line as well as two myeloid / NK cell precursor acute leukemias. In other cell lines, complete loss and an aberrant migration pattern of Rb protein expression were observed. Comparative genomic hybridization suggested that the homozygous deletions of the p15, p16 and p14 were subtle chromosomal deletions and could not be identified by standard karyotyping in some cases. Although the number of cases we analyzed was not large, alterations identified in the Rb, p53, p16, p15 and p14 genes are of significance and might be associated with tumorigenesis in NK cell neoplasms.
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PMID:Molecular analysis of tumor suppressor genes, Rb, p53, p16INK4A, p15INK4B and p14ARF in natural killer cell neoplasms. 1167 55


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