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

This brief review examines the strict relationships between cell apoptosis and G1 cyclins. It has been shown that the basic role of G1 cyclins is in regulating G1 progression and G1/S transition (the critical cycle point for cell program decisions, including apoptosis) a fatal program for cells unable to bypass G1/S checkpoint 1. Notably, both of the two giant regulators of checkpoint 1 (i.e., p105RB [retinoblastoma oncosuppressor-encoded protein] and p53 dependent WAF1/CIP1) are influenced by or influence G1 cyclins: cyclin E/cdk2 kinase complexes hyperphosphorylate p105RB, induce E2F release, and free G1 exit. On the other hand, p21-WAF1/CIP1 is an inhibitor of cyclin-dependent kinases blocking cells at G1/S. Thus, G1 cyclin activity appears as a conditio sine qua non for G1 exit and apoptosis escape.
 ...
PMID:Apoptosis and the cell cycle. 778 78

We examined a role of p53 in early B cell development using fetal liver (FL) cells from p53 deficient (-/-) mice. Expression of p53 was detected in early B lineage (pre-B) cells developed in the stromal cell-dependent FL cell culture. Proliferation of the pre-B cells from the p53(-/-) mice was augmented, suggesting that p53 negatively regulates proliferation of pre-B cells. Although p21 (WAF1/Cip1) is a downstream effector of p53 and mediates growth arrest by inhibiting the action of cyclin-dependent kinases, expression of p21 was also induced in the pre-B cells from p53(-/-) mice. These results indicate that expression of the p21 in pre-B cells is independent of p53 and that the regulatory effect of p53 on proliferation of pre-B cells is mediated by a p21-independent pathway.
 ...
PMID:p53 controls proliferation of early B lineage cells by a p21 (WAF1/Cip1)-independent pathway. 783 9

The p53 tumor suppressor gene plays a role in controlling a G1 phase checkpoint. The WAF1/CIP1 gene with encodes p21WAF1/CIP1 protein, an inhibitor of cyclin-dependent kinases, is a downstream mediator of p53 function. We examined expression of the WAF1/CIP1 gene and its relationship to growth arrest and differentiation in p53-null human leukemic cell lines. We show that p53-independent induction of WAF1/CIP1 occurs in human leukemia cells treated with 12-O-tetradecanoylphorbol-13-acetate, okadaic acid, or IFN-gamma but not with retinoic acid, vitamin D3, or DMSO. Furthermore, WAF1/CIP1 induction correlates with growth arrest associated with monocyte-macrophage differentiation. The present studies support the idea that WAF1/CIP1 gene expression can be regulated through multiple mechanisms, suggesting that strategies may be designed to restore the G1 checkpoint controls in p53-null cells by targeting these p53-independent mechanisms of WAF1/CIP1 induction.
 ...
PMID:p53-independent induction of WAF1/CIP1 in human leukemia cells is correlated with growth arrest accompanying monocyte/macrophage differentiation. 783 38

WAF1/CIP1, a gene up-regulated by p53 encodes an inhibitor of cyclin-dependent kinases. Induction of WAF1/CIP1 in cells with intact p53 is believed to be instrumental in cell cycle arrest and apoptosis caused by DNA damage. In a model system, WAF1/CIP1 has been shown to have tumor suppressive activity. It is not known however whether WAF1/CIP1 is mutated in human primary tumors. Cells from colorectal cancer have been shown to acquire a series of genetic alterations, including frequent p53 mutations. Thus colorectal tumors, particularly those without identified p53 mutations, are good candidate to search for putative WAF1/CIP1 mutations. DNA extracted from 45 tumors, (including 28 tumors for which p53 mutations had previously been searched for and not found) were PCR amplified for exon 2 of WAF1/CIP1. A search for point mutations was performed in each amplified product using a denaturing gradient gel electrophoresis (DGGE) technique which enables the efficient screening of codons 9 to 139 (i.e. 80% of the WAF1/CIP1 coding sequence). Two different DNA variants were identified and shown to be present in constitutional DNAs of the corresponding patients. The first variant, a C to A transversion at codon 31, changes a serine for an arginine and was detected in eight tumors (18% of the cases). The second variant, detected in a single case (2%) is a silent A to T transversion at the third base of codon 91. DNA extracted from 70 unrelated members from the Centre d'Etude du Polymorphisme Humain (CEPH) was screened for these polymorphisms. The ser/arg polymorphism of codon 31 was detected in seven cases (10%) thus suggesting that it is not associated with a marked colorectal cancer predisposition. The polymorphism on codon 91 was not detected. Two additional variants (arginine to histidine at position 67 and threonine to methionine at position 80) were observed once each in the CEPH family members. Somatic mutation of the WAF1/CIP1 gene was not observed, indicating that, unless there are hot spots for mutations outside the screened region, this gene is not a frequent site of point mutation in colorectal cancer.
 ...
PMID:Polymorphisms and probable lack of mutation in the WAF1-CIP1 gene in colorectal cancer. 784 85

The cloning of the negative growth regulatory gene, p21Sdi1, has led to the convergence of the fields of cellular senescence, cell cycle regulation and tumor suppression. This gene was first cloned as an inhibitor of DNA synthesis that was overexpressed in terminally non-dividing senescent human fibroblasts (SD11) and later as a p53 transactivated gene (WAF1) and a Cdk-interacting protein (CIP1, p21) that inhibited cyclin-dependent kinase activity. To identify the active region(s) of p21Sdi1, cDNA constructs encoding various deleted forms of the protein were analyzed. Amino acids 22-71 were found to be the minimal region required for DNA synthesis inhibition. Amino acids 49-71 were involved in binding to Cdk2, and constructs deleted in this region expressed proteins that were unable to inhibit Cdk2 kinase activity in vitro. The latter stretch of amino acids shared sequence similarity with amino acids 60-76 of the p27Kip1 protein, another Cdk inhibitor. Point mutations made in p21Sdi1 in this region confirmed that amino acids common to both proteins were involved in DNA synthesis inhibition. Additionally, a chimeric protein, in which amino acids 49-65 of p21Sdi1 were substituted with amino acids 60-76 of p27Kip1, had almost the same DNA synthesis inhibitory activity as the wild-type protein. The results indicate that the region of sequence similarity between p21Sdi1 and p27Kip1 encodes an inhibitory motif characteristic of this family of Cdk inhibitors.
 ...
PMID:Identification of the active region of the DNA synthesis inhibitory gene p21Sdi1/CIP1/WAF1. 785 44

p21WAF/CIP1/SDI1 is a recently identified gene expressed in cells harboring wild-type but not mutant p53 gene. It encodes a nuclear protein of 21 kD which inhibits cyclin-dependent kinase activity. Constitutive p21WAF1/CIP1/SDI1 mRNA expression was detected in neoplastic cells from patients with various hematological malignancies as well as in normal bone marrow mononuclear cells and in myeloid and lymphoid cell lines independent of their p53 status. Induced differentiation of the p53-deficient promyelocytic HL-60 cells along the monocytic lineage by phorbol ester or 1a,25 dihydroxyvitamin D3 resulted in a marked increase of both p21WAF1/CIP1/SDI1 mRNA and protein expression due to enhanced mRNA stability. Differentiation towards the granulocytic lineage by all-trans retinoic acid or dimethylsulfoxide failed to produce this effect. p21WAF1/CIP1/SDI1 is an immediate early gene since its upregulation occurred independently of de novo protein synthesis. The induction of p21WAF1/CIP1/SDI1 expression and its regulation in p53-deficient differentiating leukemic cells support the idea of an additional, p53-independent role of p21WAF1/CIP1/SDI1 in human hematopoiesis.
 ...
PMID:Posttranscriptional stabilization underlies p53-independent induction of p21WAF1/CIP1/SDI1 in differentiating human leukemic cells. 788 98

The protein p21 (WAF1, CIP1 or sdi1), induced by the tumour-suppressor protein p53, interacts with and inhibits two different targets essential for cell-cycle progression. One of these is the cyclin-Cdk family of kinases and the other is the essential DNA replication factor, proliferating-cell nuclear antigen (PCNA). We report here that separate domains of p21 are responsible for interacting with and inhibiting the two targets. An amino-terminal domain inhibits cyclin-Cdk kinases and a carboxy-terminal domain inhibits PCNA. Using these separated domains, we have determined that p21 inhibits different biological systems through different targets. The PCNA-binding domain is sufficient for inhibition of DNA replication based on simian virus 40, whereas the Cdk2-binding domain is sufficient for inhibition of DNA replication based on Xenopus egg extract and for growth suppression in transformed human cells.
 ...
PMID:Separate domains of p21 involved in the inhibition of Cdk kinase and PCNA. 788 82

Current basic research on tumorigenesis suggests that the accumulation of multiple genetic defects underlies the progression of initiated cells toward malignancy. Molecular abnormalities associated with primary brain tumors include a wide variety of changes in tumor-suppressor genes, proto-oncogenes and growth factors. A well-known tumor-suppressor gene, p53 gene, is located on the short arm (p) of chromosome 17 and consists of 11 exons transcribed into a 2.2-2.5 kb messenger (m) RNA that encode for a 53 kDa protein. Its alterations are associated with carcinogenesis of astrocytic tumors. Recent evidence suggests also that the p53 protein may function through promoting the expression of the recently discovered gene, WAF1/Cipl. Loss of chromosome 10 was frequently observed in glioblastoma. Southern blot analysis of glioblastomas revealed that 72% have the chromosome 10 loss and that 38% had amplification of the epidermal growth factor receptor (EGFR) gene. Autocrine stimulation of cell growth requires the presence of both growth factors and their receptors. Other genetic alterations in gliomas include elevated expression of the c-myc, Ha-ras, and c-fos oncogenes with a trend to increase in higher malignant grades.
 ...
PMID:Molecular changes involved in the carcinogenesis of brain tumors. 788 30

Transforming growth factor-beta (TGF-beta) inhibits cell cycle progression of many types of human cells by arresting them in the G1 phase of the cell cycle. The arrest is mediated through interactions of various cyclin-dependent protein kinases (CDKs) and their inhibitors. We demonstrate that treatment with TGF-beta induces increased levels of WAF1/Cip1/p21, a potent inhibitor of various cyclin-CDK kinase activities, in two colon cancer cell lines (LS1034 and LS513), which are sensitive to TGF-beta-induced growth arrest. The induction in at least one of these cell lines (LS1034,p53-) is p53-independent. No WAF1 induction was observed after TGF-beta treatment in a third cell line (HT-29), which is completely insensitive to the cytoinhibitory effect of TGF-beta. In both LS513 and LS1034, WAF1 induction correlated with reduced cyclin E-associated kinase activity in vitro and suppression of the retinoblastoma susceptibility gene (Rb) protein phosphorylation in vivo. In addition, WAF1 was physically associated with cyclin E in the two sensitive cell lines. These results suggest that WAF1/Cip1/p21 is a mediator of cellular sensitivity to TGF-beta.
 ...
PMID:Potential role of WAF1/Cip1/p21 as a mediator of TGF-beta cytoinhibitory effect. 789 Jun 1

There is accumulating evidence that the p53 protein contributes to tumor suppression by stimulating the transcription of specific cellular genes, such as the cell cycle control gene WAF1/ClP1. p53-mediated transcriptional activation is inhibited in cotransfection assays by overexpressed E6 protein from cancer-associated human papillomavirus (HPV) types, pointing at a possible molecular mechanism by which these viruses contribute to malignant cell transformation. Here we analysed the transcriptional transactivation function of endogenous p53 protein in a series of cervical cancer cell lines, which express the E6 gene from integrated viral sequences. Transient and stable transfection analyses employing p53-responsive reporter constructs indicated that HPV-positive cervical cancer cells contained transactivating p53 protein. Treatment of HPV-positive cells with genotoxic agents, such as mitomycin C, cisplatin, or u.v. irradiation, resulted in an increase of nuclear p53 protein levels and enhanced binding of p53 to a p53-recognition site. These effects were accompanied by an increase of WAF1/ClP1 mRNA levels. In several HPV-positive cell lines, these molecular events were linked to a cell cycle arrest in G1. In contrast, cancer cells containing mutant p53 genes did not contain transactivating endogenous p53 protein and lacked the p53-mediated response to DNA damaging agents. These results indicate that the tumorigenic phenotype of HPV-positive cancer cell lines does not necessarily correlate with a lack of basal or DNA damage induced p53 activities and that therefore the presence of high risk HPV sequences is not functionally equivalent to the loss of p53 function through somatic mutations of the p53 gene.
 ...
PMID:Functional p53 protein in human papillomavirus-positive cancer cells. 789 34


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>