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)

p21WAF1/CIP1 is a cyclin-dependent kinase inhibitor whose expression in mammalian tissues is highly induced in response to stress as well as during normal development and differentiation. Induction of p21WAF1/CIP1 in response to DNA damage occurs through a transcriptional mechanism that is dependent on the activation of the tumor suppressor protein p53. Recent evidence indicates that p21WAF1/CIP1 can also be induced independently of p53, but the signal transduction mechanisms involved in regulating p21WAF1/CIP1 expression in these situations have not been elucidated. In this study, we have addressed the role of the mitogen-activated protein kinase signaling pathway in the induction of p21WAF1/CIP1 in response to growth factor treatment. Using an experimental approach involving cotransfection of a p21WAF1/CIP1 promoter-luciferase construct with a variety of plasmids expressing dominant positive or dominant negative mutant proteins involved in this signaling pathway, we provide evidence to support a role for mitogen-activated protein kinase in the transcriptional activation of p21WAF1/CIP1 by growth factor stimulation.
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PMID:Regulation of p21WAF1/CIP1 expression through mitogen-activated protein kinase signaling pathway. 854 69

The WAF1/CIP1 protein has been identified as a downstream mediator of the tumor suppressor p53 in regulating cell cycle progression through a G1-phase check-point. Recent work has implicated the functional status of p53 as a critical determinant in the apoptotic response of certain cell lines to DNA damaging agents. By using human T-cell leukemia virus type I-transformed lymphoid cell lines that differ in their level and function of wild-type p53, we investigated the induction of WAF1/CIP1 and apoptosis after exposure to Adriamycin, a genotoxic agent. We found that regardless of the p53 status in these cell lines, WAF1/CIP1 RNA was rapidly induced in response to Adriamycin treatment. An elevated level of WAF1/CIP1 protein was observed as well. Additionally, we demonstrated that apoptosis was induced in all cell lines analyzed despite some having functionally inactive p53 protein. Our data suggest that a p53-independent pathway may play a role in the apoptotic response observed in some cell lines after exposure to DNA damaging agents.
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PMID:Induction of the WAF1/CIP1 protein and apoptosis in human T-cell leukemia virus type I-transformed lymphocytes after treatment with adriamycin by using a p53-independent pathway. 855 18

One way in which wild-type p53 is able to regulate cell cycle progression is thought to be via the induction of its downstream target gene Waf1/CIP1, thus indirectly regulating the transcriptional activity of E2F. The E2F transcription factors are known to be key effectors of the cell cycle. We report here that there is a physical and functional interaction between p53 and two of the components of the E2F transcription factors, E2F1 and DP1. The expression of wild-type p53 can inhibit the transcriptional activity of E2F, and the expression of both E2F1 and DP1 can also downregulate p53-dependent transcription. The transcriptional activity of p53 is known to be inhibited by the direct binding of mdm2, but we demonstrate here that both E2F1 and DP1 can inhibit p53 transcriptional activity independently of mdm2. Detailed studies of protein-protein interactions have provided evidence that E2F1 and its co-operating factor DP1 can complex with p53 both in vitro and in vivo.
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PMID:Physical and functional interactions between p53 and cell cycle co-operating transcription factors, E2F1 and DP1. 855 38

The Waf1/Cip1 protein induces cell cycle arrest through inhibition of the activity of cyclin-dependent kinases and proliferating cell nuclear antigen. Expression of the WAF1/CIP1 gene is induced in a p53-dependent manner in response to DNA damage but can also be induced in the absence of p53 by agents such as growth factors, phorbol esters, and okadaic acid. WAF1/CIP1 expression in U937 human leukemic cells is induced by both phorbol ester, a protein kinase C activator, and by okaidaic acid, an inhibitor of phosphatases 1 and 2A. Both of these agents induce the differentiation of these leukemic cells toward macrophages. We demonstrate that phorbol esters and okadaic acid stimulate transcription from the WAF1/CIP1 promoter in U937 cells. This transcription is mediated by a region of the promoter between -154 and +16, which contains two binding sites for the transcription factor Sp1. Deletion or mutation of these Sp1 sites reduces WAF1/CIP1 promoter response to phorbol ester and okadaic acid, while a reporter gene under the control of a promoter containing only multiple Sp1 binding sites and a TATA box is induced by phorbol ester and okadaic acid. The WAF1/CIP1 promoter is also highly induced by exogenous Sp1 in the Sp1-deficient Drosophila Schnieder SL 2 cell line. These results suggest that phorbol ester and okadaic acid activate transcription of the WAF1/CIP1 promoter through a complex of proteins that includes Sp1 and basal transcription factors.
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PMID:The role of the transcription factor Sp1 in regulating the expression of the WAF1/CIP1 gene in U937 leukemic cells. 855 3

The hormonal form of vitamin D, 1,25-dihydroxyvitamin D3, acting through its cognate nuclear receptor (vitamin D3 receptor, VDR) will induce myeloid leukemic cell lines to terminally differentiate into monocytes/macrophages. Because VDR acts by transcriptionally regulating responsive genes in a ligand-dependent manner, we sought target genes of the receptor that initiate, the differentiation process in response to ligand. We screened a cDNA library prepared from the myelomonocytic U937 cell line with probes generated from either 1,25-dihydroxyvitamin D3-treated or untreated cells. We report here that a candidate clone that hybridized differentially is the Cdk inhibitor p21WAF1, CIP1. Furthermore, we show that p21 is transcriptionally induced by 1,25-dihydroxyvitamin D3 in a VDR-dependent, but not p53-dependent, manner, and we identify a functional vitamin D response element in the p21 promoter. Transient overexpression of p21 and/or the related Cdk inhibitor p27 in U937 cells in the absence of 1,25-dihydroxyvitamin D3 results in the cell-surface expression of monocyte/macrophage-specific markers, suggesting that ligand-modulated transcriptional induction of the p21 gene facilitates the induced differentiation of this monoblastic cell line. We believe that this is the first report demonstrating that the ectopic overexpression of a Cdk inhibitor such as p21 or p27 directly leads to a terminal differentiation program.
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PMID:Transcriptional activation of the Cdk inhibitor p21 by vitamin D3 leads to the induced differentiation of the myelomonocytic cell line U937. 856 48

p21(WAF1/CIP1/SDI1), an inhibitor of cyclin-dependent kinases, is expressed at varying levels in human adrenal glands removed during surgery or organ recovery. In glands with p21 mRNA, nuclear p21 immunoreactivity, which was occasionally extensive, colocalized with p53 immunoreactivity and DNA damage, as evidenced by in situ end-labeling. Many cells showed morphological features of apoptosis when observed by fluorescent DNA dye staining and electron microscopy. This pattern was also associated with high levels of cytoplasmic heat shock protein 70. To address the question of the origin of p21 expression in some human adrenal glands, rat adrenal glands were subjected to 30 min of ischemia followed by 8 h of reperfusion. Cells with nuclear p21 and p53 appeared in the adrenal cortex together with DNA damage detected by in situ end-labeling. Nuclear p21 immunoreactivity was also produced in adrenal tissue fragments incubated at 37 degrees C in vitro. However, in this case, p21 expression was confined to the cut edge of the tissue. In contrast, p21 in human adrenal glands, as in ischemic rat glands, was within the inner regions of the cortex, supporting an origin of the protein in vivo rather than postmortem. The p53/p21 pathway of reaction to cellular injury, potentially leading to apoptosis, may play a role in tissue damage such as that resulting from ischemia/reperfusion. In the human adrenal cortex this process may be a precursor of adrenal failure.
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PMID:Expression of p21(WAF1/CIP1/SDI1) and p53 in apoptotic cells in the adrenal cortex and induction by ischemia/reperfusion injury. 860 38

Cells with a functional p53 pathway undergo a G0/G1 arrest or apoptosis when treated with gamma radiation or many chemotherapeutic drugs. It has been proposed that DNA damage is the exclusive signal that triggers the arrest response. However, we found that certain ribonucleotide biosynthesis inhibitors caused a p53-dependent G0 or early G1 arrest in the absence of replicative DNA synthesis or detectable DNA damage in normal human fibroblasts. CTP, GTP, or UTP depletion alone was sufficient to induce arrest. In contrast to the p53-dependent response to DNA damage, characterized by long-term arrest and irregular cellular morphologies, the antimetabolite-induced arrest was highly reversible and cellular morphologies remained relatively normal. Both arrest responses correlated with prolonged induction of p53 and the Cdk inhibitor P21(WAF1/CIP1/SDI1) and with dephosphorylation of pRb. Thus, we propose that p53 can serve as a metabolite sensor activated by depletion of ribonucleotides or products or processes dependent on ribonucleotides. Accordingly, p53 may play a role in inducing a quiescence-like arrest state in response to nutrient challenge and a senescence-like arrest state in response to DNA damage. These results have important implications for the mechanisms by which p53 prevents the emergence of genetic variants and for developing more effective approaches to chemotherapy based on genotype.
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PMID:A reversible, p53-dependent G0/G1 cell cycle arrest induced by ribonucleotide depletion in the absence of detectable DNA damage. 860 41

The intracellular calcium pump sarco(endo)plasmic reticulum Ca2+ (SERCA) is responsible for the formation of the Ca2+ gradient across the endoplasmic reticulum membrane, and this gradient is used to generate the Ca2- signal during agonist-stimulated cell growth. In the present study, the role of SERCA in both cell cycle and growth control was investigated using cultured rat aortic endothelial cells (RAEC). Using a novel DNA transfection approach, cell lines were established that showed varying degree of SERCA activity through the down-regulation of the endogenous SERCA gene (B. F. Liu, X. Xu, R. Fridman, S. Muallem, and T. H. Kuo, J. Biol. Chem. 271, 1--9, 1996). Cell proliferation studies indicated that the lower SERCA expressing cells exhibited a slower growth pattern without altering the doubling time which was similar for both parental and transfected RAEC lines. G1 to S phase transition was prolonged with a smaller proportion of cells entering DNA synthesis as indicated by thymidine incorporation assay. Comparison of transfected cell lines indicated a tight coupling of SERCA activity and the length of the G1 period. Down-regulation of SERCA gene expression was accompanied by increased mRNA levels of p21 (WAF1/CIP1), a universal cell cycle inhibitor. The delay in G1 to S progression also coincided with the up-regulation of p53 mRNA and underphosphorylation of the retinoblastoma protein. This study suggests that Ca2+ metabolism in the agonist mobilizable pool controls the cell cycle through the regulation of genes operating in the critical G1 to S checkpoint.
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PMID:The exit from G(0) into the cell cycle requires and is controlled by sarco(endo)plasmic reticulum Ca2+ pump. 861 36

A proportion of the population is exposed to acute doses of ionizing radiation through medical treatment or occupational accidents, with little knowledge of the immediate effects. At the cellular level, ionizing radiation leads to the activation of a genetic program which enables the cell to increase its chances of survival and to minimize detrimental manifestations of radiation damage. Cytotoxic stress due to ionizing radiation causes genetic instability, alterations in the cell cycle, apoptosis, or necrosis. Alterations in the G1, S and G2 phases of the cell cycle coincide with improved survival and genome stability. The main cellular factors which are activated by DNA damage and interfere with the cell cycle controls are: p53, delaying the transition through the G1-S boundary; p21WAF1/CIP1, preventing the entrance into S-phase; proliferating cell nuclear antigen (PCNA) and replication protein A (RPA), blocking DNA replication; and the p53 variant protein p53 as together with the retinoblastoma protein (Rb), with less defined functions during the G2 phase of the cell cycle. By comparing a variety of radioresistant cell lines derived from radiosensitive ataxia telangiectasia cells with the parental cells, some essential mechanisms that allow cells to gain radioresistance have been identified. The results so far emphasise the importance of an adequate delay in the transition from G2 to M and the inhibition of DNA replication in the regulation of the cell cycle after exposure to ionizing radiation.
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PMID:Regulation of the cell cycle following DNA damage in normal and Ataxia telangiectasia cells. 862 Sep 34

The CDK-inhibitor p21WAF1/CIP1 has been implicated as a growth arrest mediator in p53-tumour suppression, cellular senescence and terminal differentiation. Cell type specific differences in p53-independent p21 expression and cell cycle arrest were found following treatment of human tumour cell lines with serum, 12-O-tetradecanoyl-phorbol-13-acetate (TPA), or okadaic acid (OA). TPA induced p21 in ML1, K562 and HL60 leukemia cells, whereas OA induced p21 in SW480 and GM4723 carcinoma cells as well as in leukemic cells. In addition, TPA- and serum- but not OA-induced cell cycle arrest was reversed upon return of p21 to basal levels. To further investigate the mechanisms underlying p53-independent regulation of p21, the transcription inhibitor, Actinomycin D (AMD), was used to block p21 expression. The results showed a complete inhibition of p21 mRNA and protein induction by TPA or adriamycin but little effect on p21 mRNA induced by OA in the presence of AMD. These results suggested that TPA-induced p21 expression requires transcription initiation, while a post-transcriptional mechanism may be involved in OA-induction as well. Transient transfection assays with p21 promoter-luciferase reporters and TPA or OA treatment further confirmed that TPA, and to a lesser extent, OA, initiated transcription of p21. Finally, the protein kinase C inhibitor, staurosporine, was found to interfere with p21 induction and prevent cell cycle arrest following treatment with TPA but not OA, suggesting a requirement for PKC in TPA activation of p21 expression.
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PMID:Regulation of p21WAF1/CIP1 expression by p53-independent pathways. 862 72


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