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 cyclin dependent kinase inhibitor, p21, is a multifunctional protein involved in coordinating the cellular response to negative growth signals. Induced by cellular damage under the transcriptional control of the p53 tumour suppressor protein, p21 interfaces with a number of cellular proteins involved in growth control. Although p21 has a diverse range of activities, from assembly factor to transcriptional modulator, its ability to interact with and regulate the activity of the cyclin dependent protein kinases is paramount to many of these functions.
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PMID:p21: structure and functions associated with cyclin-CDK binding. 955 11

The p16INK4A/CDKN2/MTS1 gene encodes a specific inhibitor of cyclin-dependent kinases (CDKs) 4 and 6. This study investigates p16INK4A gene status and expression in mesenchymal tumours, in particular soft tissue sarcomas (STSs). Employing non-radioactive polymerase chain reaction-single strand conformational polymorphism (PCR-SSCP) sequencing, no p16INK4A mutation was found in 86 samples taken from 74 mesodermal tumours with known p53 gene status. This suggests that p16INK4A gene alterations, inc contrast to p53, are not involved in the progression of STS. This finding is supported by the reports of a low frequency of deletions and intragenic mutations in STS. Furthermore, by immunohistochemistry (IHC), an inverse correlation was established between p16INK4A and RB positivity for 62 per cent of the frozen tumour samples investigated. However, alterations in other components of the pRh/p16INK4A/ CDK4/cyclin D1/E2F pathway have been proven crucial for tumourigenesis in human sarcomas.
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PMID:No p16INK4A/CDKN2/MTS1 mutations independent of p53 status in soft tissue sarcomas. 958 21

The novel human pre-B cell line OZ was established from a patient with an aggressive form of non-Hodgkin's lymphoma. Karyotypic analysis of both the primary tumour and OZ cells revealed several marker chromosomes, including the t(14;18)(q32;q21) translocation, which involves the Bcl-2 gene, and alterations on chromosome 17p. Southern blot analysis found identical rearrangements in the 5' region of Bcl-2 gene in the primary tumour and OZ cells. Homozygous deletions of the p15INK4B and p16INK4A genes, however, were present only in OZ cells. Western blot analysis detected aberrant small molecular-weight p53 proteins in both cell types. In addition, OZ cells no longer expressed the CD20 antigen. These findings suggest that Bcl-2 gene rearrangement and aberrant p53 expression resulted in the original B-cell tumour. A subsequent transforming event involving the p15INK4B and p16INK4A genes may have generated more immature cells with a growth advantage during in vitro culture. The genetic alterations involving p53, p15INK4B, and p16INK4A may be implicated in the aggressive form of t(14;18)(q32;q21)-bearing tumours and their poor prognosis.
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PMID:Establishment of a novel human B-cell line (OZ) with t(14;18)(q32;q21) and aberrant p53 expression was associated with the homozygous deletions of p15INK4B and p16INK4A genes. 960 Jan 10

Cyclin-dependent kinase (CDK) inhibitor genes have recently been proposed as new tumor suppressor genes. To define the possible participation of CDK inhibitor genes in lung carcinogenesis, we investigated the alterations of p15INK4B, p16INK4A, p21Waf1, and p27Kip1 genes in 34 human lung cancer cell lines using the polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP), direct sequencing, and southern dot blot methods. Among the four CDK inhibitor genes, alterations of only the p16INK4A gene were found in 8 out of 34 (24%) cell lines, and all eight cell lines having a p16INK4A gene alteration had an alteration of either the K-ras of p53 gene. Conversely, p16INK4A gene alterations were found in none of the 3 cell lines having Rb gene alterations and none of the 3 cell lines having amplification of the N-myc gene. Polymorphism was found in both p21Waf1 and p27Kip1 genes, but no association was found between the polymorphism and alterations of other genes. These results suggest that p16INK4A gene alterations may play a certain role for lung carcinogenesis in co-operation with either K-ras or p53 gene alterations.
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PMID:Coincidental alterations of p16INK4A/CDKN2 and other genes in human lung cancer cell lines. 967 67

Tumour formation relies on a complex combination of genetic and environmental factors. In particular, the contributions from inherited predisposition genes as well as carcinogens, for example from cigarettes or in the diet, are amongst the major contributors to tumorigenesis. Since the study of such processes in particularly difficult in human cancers, the availability of a well-defined model system is of obvious benefit. The mouse skin model of multistage carcinogenesis offers an excellent tool for the study of the target cells, the target genes and the biological events associated with neoplasia. In this system, tumorigenesis occurs in a series of defined stages, each of which is characterized by specific and reproducible alterations in genes such as H-ras, cyclin D1, p53 and p16INK4A. Additional changes occur in the production of, or response to, factors such as transforming growth factor beta (TGF beta). These genetic and biological alterations are mirrored in human tumours of epithelial origin. Hence, research into the general principles of tumour initiation, promotion and progression in the context of the mouse skin model is likely to prove valuable in the continual search for new methods for the diagnosis, prevention, and therapeutic treatment of human cancers.
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PMID:Epithelial carcinogenesis in the mouse: correlating the genetics and the biology. 968 81

This review summarizes data on the occurrence, the trends, and the life-style, environmental, occupational and genetic determinants of pancreatic cancer. Epidemiologic evidence implicates tobacco smoking as one cause. The evidence regarding alcohol consumption is inconsistent. Although both positive and inconclusive findings are encountered, the bulk of the evidence on coffee consumption is negative. Fat intake is linked with obesity and diabetes mellitus, which are risk factors for pancreatic cancer. Fruit and vegetable consumption appears to be protective. No occupational or environmental agent has been confirmed to increase the risk, but epidemiologic evidence is inconsistent, Little is known about the role of genetic polymorphisms of metabolic enzymes in pancreas carcinogenesis. Pancreatic cancer shows high rates of mutations of Ki-ras and losses or mutations of tumor suppressor genes (p53, p16INK4A, and SMAD4/DPC-4). Ki-ras mutations have been associated with life-style factors in relation to pancreatic cancer, but the evidence is still scant and inconsistent.
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PMID:Occurrence, trends and environment etiology of pancreatic cancer. 971 Mar 67

The p16IN4/CDKN2/MTS1 gene encodes two structurally different proteins: a cyclin-dependent kinase inhibitor called p16INK4a, which regulates retinoblastoma protein-dependent G1 arrest, and a cell cycle inhibitor designated p19ARF, which arrests cell growth in G1-S and also in G2-M. Whereas inactivation of p16INK4a has been described as a frequent event in lung cancer, the current function of p19ARF is still poorly understood. We have examined the expression of the human p19ARF (hp19ARF) protein in a large series of lung cancers using immunohistochemistry and showed that the protein was more frequently lost in high-grade neuroendocrine (NE) lung tumors (large cell NE carcinoma and small cell lung carcinoma; 51 of 78, 65%) than it was in non-small cell lung cancer (25 of 101, 25%). No deleterious mutation was found in exons 1beta and 2 of hp19ARF in those NE tumors with negative immunoreactivity, and a beta transcript was detected in the majority of them. Concomitant absence of hp19ARF and retinoblastoma proteins was frequently detected in high-grade NE lung tumors, whereas no relationship could be found between the status of hp19ARF and p53 proteins in those tumors. These results are consistent with an alternative growth suppressor function for hp19ARF in NE lung cancer that is distinct from that of p16INK4a. Moreover, the frequent uncoupling between the beta transcript and the hp19ARF protein suggests a novel mechanism of inactivation at the translational level.
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PMID:The human p19ARF protein encoded by the beta transcript of the p16INK4a gene is frequently lost in small cell lung cancer. 973 4

Carcinoma in ulcerative colitis (UC) develops from dysplastic precursor lesions, which include flat dysplasia (FD) and polypoid dysplasias (PD). PD may present as single or multiple polypoid structures or as plaque-like lesions that, independent of histological grade, are an indication for colectomy. PDs are histologically similar to adenomas and may not be readily distinguished by light microscopy. It is not known whether FD and PD are different entities, or whether they represent etiologically similar lesions with different morphological expression. We microdissected 25 cases of UC with PD and 19 samples of FD with surrounding chronic colitis (CC) in UC. Loss of heterozygosity (LOH) at the von Hippel Lindau (vHL) gene locus and the putative tumor suppressor genes APC, INK4A (9p16), and p53 was studied. LOH of the vHL gene, INK4A (9p16), and APC was also studied in 11 sporadic adenomas of the colon. LOH at the vHL locus was present in 50% of the samples of PD and in 12% of the samples of FD. LOH was seen in CC close to PD and FD in 26% and 12% of cases, respectively. No adenoma showed LOH of the vHL gene markers studied. LOH in p53 was seen in PD in 16% cases and in FD in 42% cases and in CC close to PD and FD in 0% and 14% cases, respectively. LOH patterns between PD and FD of the markers for APC and 9p16 were not different. LOH in APC was seen in two of five cases of adenoma. We conclude that PD and FD share genetic alterations in APC and 9p16 genes. More frequent involvement of the VHL gene in PD and surrounding CC and involvement of p53 in HGD and CC in FD may represent genetic differences between the development of PD and FD and may be the cause of the different morphology. The infrequency of LOH at the vHL locus in adenomas versus PD may serve as a discriminator between adenomas and PD in diagnostically problematic cases.
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PMID:Loss of heterozygosity of the von Hippel Lindau gene locus in polypoid dysplasia but not flat dysplasia in ulcerative colitis or sporadic adenomas. 974 12

In man, the MTS1 (multiple tumor suppressor 1) locus has been located on chromosome band 9p21 and encodes two unrelated genes, p16INK4a and p19ARF that both act, through different mechanisms, as cell proliferation inhibitors. The inhibitory mechanism of p19ARF has begun to be elucidated by the finding that the protein has the ability to bind the mdm2 oncoprotein. mdm2 is implicated in the degradation of p53 and its functional inactivation. While this result provides an opportunity for understanding the tumor suppression role of p19ARF, it allows to define a new cell cycle regulatory pathway, the p19ARF-p53 pathway. In this respect, MTS1 is unique in its ability to control two crucial pathways that regulate the cell cycle. For this reason, it will be crucial to investigate the status of p19ARF in a variety human tumors.
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PMID:[When p19ARF finds a partner or new "dangerous liaisons"]. 975 79

Functional inactivation of the retinoblastoma (RB) and p53 pathways appears to be a rite of passage for all cancerous cells and results in disruption of cell-cycle regulation and deactivation of the apoptotic response that normally ensues. The INK4a/ARF locus sits at the nexus of these two growth-control pathways, by virtue of its ability to generate two distinct products: the p16INK4a protein, a cyclin-dependent kinase inhibitor that functions upstream of RB; and the p19ARF protein, which blocks MDM2 inhibition of p53 activity. This 'one gene--two products--two pathways' arrangement provides a basis for the prominence of INK4a/ARF in tumorigenesis.
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PMID:The INK4a/ARF tumor suppressor: one gene--two products--two pathways. 975 29


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