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)

Wildtype and mutant v-Myc proteins were overexpressed in Escherichia coli using the T7 RNA polymerase system, and the in vitro DNA-binding activities of partially or highly purified proteins were analysed by native DNA-cellulose chromatography. For the construction of the expression plasmids, cloned proviral DNA from wildtype MC29 or from its spontaneous deletion mutant Q10C was used, the latter lacking internal v-myc sequences. Both the wildtype (p59) and the mutant (p42) recombinant protein contain at their amino termini 12 amino acids encoded by the vector, followed by 11 gag amino acids and 9 amino acids encoded by v-myc sequences derived from noncoding c-myc sequences. In addition, p59 contains 416 amino acids encoded by v-myc sequences derived from the complete chicken c-myc coding region, whereas p42 lacks 120 amino acids from the central region of the Myc protein including the highly acidic domain. Two additional proteins were engineered which contain the first 309 (p53) or the last 107 (p16) amino acids, respectively, of the Myc protein sequence in addition to vector-encoded amino acids. The p16 protein represents the carboxyl terminus of the Myc protein sequence containing both a muscle determination gene (MyoD1) homology region, including a basic motif and an amphipathic helix-loop-helix motif, and a leucine heptad repeat. All proteins, except p53 which lacks the carboxyl-terminal Myc protein sequences, bound to native DNA-cellulose and were eluted with 200-500 mM NaCl. Based on the DNA-binding activities of recombinant or spontaneous mutant v-Myc proteins extracted from bacterial or from transformed avian cells, we conclude that the DNA-binding domain of avian Myc proteins is confined within the last 86 carboxyl-terminal amino acids. The same region is also shown to be necessary and sufficient for Myc protein dimerization. This 86-amino acid region essentially encompasses a putative basic DNA contact surface and a tandem array of two presumed protein dimerization motifs, helix-loop-helix and leucine repeat.
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PMID:Myc protein structure: localization of DNA-binding and protein dimerization domains. 199 48

Purified virions of tick-borne encephalitis (TBE) virus contain 3 proteins, V1, V2 and V3, with molecular weights of 8 000, 13 000 and 53 000 daltons, respectively. Seven virus-specific polypeptides were revealed in TBE-virus infected continuous pig embryo kidney cells, namely p93-96, p79, p69, p53, p47, p16 and p13 (pN designating polypeptide with a mol wt of N X 1 000 daltons). Proteins p93-96, p69, p53, p47 and p13 corresponded by their mol wt to proteins NV5, NV4, V3 and V2 (NV1 1/2) of mosquito-borne flaviviruses. Protein p79, designated NV4 1/2, and protein p16 (the only virus-specific protein inhibited by hypertonic NaCl concentrations), had no analogues among proteins of mosquito-borne flaviviruses. The possibility of a cellular origin of protein p47 (NV3) is discussed.
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PMID:Synthesis of virus-specific proteins in tick-borne encephalitis virus-infected pig embryo kidney cells. 610 57

To evaluate the role of p16 multiple tumor suppressor (MTS1) and p53 protein in human radiation-induced skin cancer, we examined the expression of p16 and p53 in eight cases using immunohistochemistry. An abnormal location of p16 expression in the cytoplasm was found in seven of eight cases, but the expression of p53 in nuclei was noted in only three of eight cases. These findings suggest that the inactivation of p16 might be related to its binding with another unknown oncoprotein in the cytoplasm and thus lead to carcinogenesis.
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PMID:Abnormal location of p16 protein and overexpression of p53 protein in human radiation-induced skin cancer. 747 71

Changes which lead to excessive cyclin production or to loss of cell cycle inhibition by proteins such as p16/MTS1 may release breast tumour cells from the constraints of cell division. In order to establish the frequency of MTS1/p16 gene alteration and its relation with genetic damage to the p53 and cyclin D1 genes, we have studied these gene abnormalities in 164 human primary breast cancers and in six breast cancer cell lines. Two breast cancer cell lines and one primary tumour showed a homozygous deletion of exon 2 of the MTS1 gene. Using single-strand conformation polymorphism and subsequent sequencing analysis, one tumour showed an alteration at codon 67 (CCC-->CTC; Pro to Leu). Another tumour showed a mutation at codon 98 (without amino acid change) with an additional polymorphism at codon 140. This polymorphism was also found in 13 other tumour samples, but has no effect on (disease-free) survival. From these data we conclude that the occurrence of CDKN2 (p16/MTS1) mutation in primary breast cancer is a rare event and is not likely to be involved in human breast tumour carcinogenesis and progression.
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PMID:Infrequent CDKN2 (MTS1/p16) gene alterations in human primary breast cancer. 754 49

This review attempts to provide current information on the role played by the p53 gene in normal and leukemic hematopoiesis with particular emphasis on chronic myeloid leukemia. On the basis of the currently available data we can argue that p53 acts as a negative regulator of proliferation of myeloid mature cells and CD34+ progenitors, and its action is mediated through changes in cell cycle kinetics, mainly before the S phase. The p53-dependent pathway is also regulated by several proteins, including p16, p21, p27 (cyclin-dependent kinase [CDK] inhibitors), and a few oncogenes (bcl-2, bax, MDM-2). Although there is some information about the changes in the p53 gene seen in various types of leukemia, the functions and biological importance of these changes in the pathogenesis of leukemia are still largely elusive. During the past several years, accumulated evidence suggests that changes in the p53 gene are commonly associated with blast crisis of chronic myeloid leukemia (CML) but rarely with chronic phase, and they are represented by rearrangements, deletions and point mutations. As for most of the tumors, the majority of point mutations occur between exons 4 and 8 (hot regions). In patients with CML in blastic crisis the most frequent mechanism of p53 inactivation is complete deletion of one allele in association with a point mutation in the remaining allele.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Role of p53 in leukemogenesis of chronic myeloid leukemia. 754 4

B-cell chronic lymphocytic leukemia (B-CLL) samples were screened for alterations in multiple tumor suppressor genes (p53 (17p13), p16INK4 (9p21), and disrupted in B-cell malignancy (DBM) (13q14) by using polymerase chain reaction-based assays. Eleven percent (11 of 96) of the B-CLL cases analyzed in this study and a previous study had mutations in the p53 gene. In contrast, analysis of the p16 gene showed none of 80 B-CLL cases had mutations and five cases (6%) had homozygous deletions. Deletions of 13q14 (DBM) occurred in 18% (17 of 96) of patients surveyed. Thus, 28 of 96 cases showed an alteration in one or more of the three tumor suppressor loci examined. However, cases with p53 mutations rarely showed simultaneous loss of DBM. Our results suggest that inactivation of the tumor suppressor genes p53 and DBM may be mutually exclusive, thus providing alternate pathways for tumor development in B-CLL patients.
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PMID:Alterations of multiple tumor suppressor genes (p53 (17p13), p16INK4 (9p21), and DBM (13q14)) in B-cell chronic lymphocytic leukemia. 757 5

Diffusely infiltrating low-grade astrocytomas (WHO grade II) have an intrinsic tendency for progression to anaplastic astrocytoma (WHO grade III) and glioblastoma (WHO grade IV). This change is due to the sequential acquisition of genetic alterations, several of which have recently been identified. In low-grade astrocytomas, p53 mutations with or without loss of heterozygosity on chromosome 17p are the principal detectable change. Anaplastic astrocytomas contain p53 mutations at an overall incidence of 34% and, in addition, loss of heterozygosity on chromosome 19q and frequent homozygous deletion of the p16 tumor suppressor (MTS-1) gene. The most malignant astrocytic neoplasms, the glioblastoma, further shows loss of chromosome 10 and amplification of the epidermal growth factor receptor (EGF-R) gene at overall incidences of 66% and 34%, respectively. The type and distribution of p53 mutations in astrocytic brain tumours are not suggestive of specific environmental carcinogens operative in their aetiology. Analysis of 91 families with p53 germline mutations reported to date show that tumours of the nervous system account to 12% of all neoplasms. Of a total of 57 brain tumours reported, 30 were classified histologically and of these, 73% were of astrocytic origin. The observation that somatic p53 mutations in sporadic brain tumours are largely restricted to those of astrocytic origin and that astrocytomas also prevail among CNS neoplasms associated with p53 germline mutation strongly suggests, that p53 mutations are capable of initiating neoplastic transformation in astrocytes of the human nervous system.
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PMID:Genetic alterations associated with the evolution and progression of astrocytic brain tumours. 758 39

The MTS1 gene on chromosome 9p21 encodes the p16 inhibitor of cyclinD/Cdk-4 complexes, and is deleted or mutated in a variety of tumour types. We found allelic deletions of 9p21-p22 in 85% of pancreatic adenocarcinomas. Analysis of MTS1 in pancreatic carcinomas (27 xenografts and 10 cell lines) showed homozygous deletions in 15 (41%) and sequence changes in 14 (38%). These included eight point mutations (four nonsense, two missense and two splice site mutations) and six deletions/insertions, all accompanied by loss of the wild-type allele. Sequencing of MTS1 from primary tumours confirmed the mutations. Coexistent inactivations of both MTS1 and p53 was common and suggests that abnormal regulation of cyclin-dependent kinases may play an important role in the biology of pancreatic carcinoma.
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PMID:Frequent somatic mutations and homozygous deletions of the p16 (MTS1) gene in pancreatic adenocarcinoma. 772 12

The 9p21 region of human chromosome 9 is a hot spot for chromosomal aberrations in both cultured cell lines and primary tumors. This region contains a gene, P16 (also called MTS1, CDKN2 and p16INK4), that encodes a presumptive negative cell cycle regulator called p16. P16 is deleted or mutated at high frequency in a variety of tumor cell lines including melanoma and bladder carcinoma lines. As such, it is likely to be a tumor suppressor gene. Here we show that P16 is mutated in primary bladder carcinomas (3 of 33) and melanomas (5 of 34). These findings support studies that show P16 mutations are not solely a product of growth in tissue culture but rather are involved in formation of tumors in viva. Some bladder primary tumors and some bladder and melanoma tumor cell lines contain mutations in both P16 and P53 at frequencies that suggest that p53 and p16 function in different pathways, each of which is important in suppressing malignant transformation.
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PMID:Genetic evidence in melanoma and bladder cancers that p16 and p53 function in separate pathways of tumor suppression. 774 14

The transforming growth factor beta s (TGF-beta s) are a group of multifunctional growth factors which inhibit cell cycle progression in many cell types. The TGF-beta-induced cell cycle arrest has been partially attributed to the regulatory effects of TGF-beta on both the levels and the activities of the G1 cyclins and their kinase partners. The activities of these kinases are negatively regulated by a number of small proteins, p21 (WAF1, Cip1), p27Kip1, p16, and p15INK4B, that physically associate with cyclins, cyclin-dependent kinases, or cyclin-Cdk complexes. p21 has been previously shown to be transcriptionally induced by DNA damage through p53 as a mediator. We demonstrate that TGF-beta also causes a rapid transcriptional induction of p21, suggesting that p21 can respond to both intracellular and extracellular signals for cell cycle arrest. In contrast to DNA damage, however, induction of p21 by TGF-beta is not dependent on wild-type p53. The cell line studied in these experiments, HaCaT, contains two mutant alleles of p53, which are unable to activate transcription from the p21 promoter when overexpressed. In addition, TGF-beta and p53 act through distinct elements in the p21 promoter. Taken together, these findings suggest that TGF-beta can induce p21 through a p53-independent pathway. Previous findings have implicated p27Kip1 and p15INK2B as effectors mediating the TGF-beta growth inhibitory effect. These results demonstrate that a single extracellular antiproliferative signal, TGF-beta, can act through multiple signaling pathways to elicit a growth arrest response.
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PMID:Transforming growth factor beta induces the cyclin-dependent kinase inhibitor p21 through a p53-independent mechanism. 777 46


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