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)

Normal cells do not divide indefinitely due to a process known as replicative senescence. Human cells arrest growth with a senescent phenotype when they acquire one or more critically short telomeres as a consequence of cell division. Recent evidence suggests that certain types of DNA damage, chromatin remodeling, and oncogenic forms of Ras or Raf can also elicit a senescence response. We show here that E2F1, a multifunctional transcription factor that binds the retinoblastoma (pRb) tumor suppressor and that can either promote or suppress tumorigenesis, induces a senescent phenotype when overexpressed in normal human fibroblasts. Normal human cells stably arrested proliferation and expressed several markers of replicative senescence in response to E2F1. This activity of E2F1 was independent of its pRb binding activity but dependent on its ability to stimulate gene expression. The E2F1 target gene critical for the senescence response appeared to be the p14(ARF) tumor suppressor. Replicatively senescent human fibroblasts overexpressed p14(ARF), and ectopic expression of p14(ARF) in presenescent cells induced a phenotype similar to that induced by E2F1. Consistent with a critical role for p14(ARF), cells with compromised p53 function were immune to senescence induction by E2F1, as were cells deficient in p14(ARF). Our findings support the idea that the senescence response is a critical tumor-suppressive mechanism, provide an explanation for the apparently paradoxical roles of E2F1 in oncogenesis, and identify p14(ARF) as a potentially important mediator of the senescent phenotype.
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PMID:Regulation of a senescence checkpoint response by the E2F1 transcription factor and p14(ARF) tumor suppressor. 1059 30

E2F transcriptional activity controls the expression of many of the genes required for G1 to S phase progression. E2F1, one member of the E2F family, plays an important role in the induction of apoptosis. We have examined the role of the E2F1 transcription factor in apoptosis during T-cell maturation in the thymus. We show that E2F1 is required for the apoptosis of autoimmune immature T cells during thymic negative selection in vivo. This T-cell receptor-mediated apoptosis coincides with the E2F1-dependent increase of p19-ARF mRNA and p53 protein levels. In contrast, E2F1 is not required for the induction of apoptosis by glucocorticoids or DNA damage. These results demonstrate a specific role for E2F1, which triggers a pathway leading to ARF and p53 induction, in a physiological apoptosis pathway that is uncoupled from a normal proliferative event.
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PMID:A role for E2F1 in the induction of ARF, p53, and apoptosis during thymic negative selection. 1061 8

We recently reported that E2F1 could transactivate the p21 promoter via cis-acting elements between -119 to +16 bp of the p21 gene. Here we show that activated V12-H-Ras can induce the p21 promoter through the same region of the p21 promoter by a p53-independent mechanism in NIH3T3 cells. In contrast, activated Ras was not able to induce the p21 promoter in E2F1-/- fibroblasts, suggesting that E2F1 is required for induction of the p21 promoter by activated Ras. Cotransfection of increasing concentrations of dominant negative E2F1 alone, or with dominant negative DP1 into NIH3T3 cells suppressed induction of the p21 promoter by activated Ras. These data suggest that p53-independent induction of the p21 promoter by activated Ras is mediated at least in part by E2F1. Oncogene (2000) 19, 961 - 964.
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PMID:A role for E2F1 in Ras activation of p21(WAF1/CIP1) transcription. 1070 5

The necdin gene is expressed predominantly in postmitotic neurons and encodes a growth suppressor that interacts with the transcription factors E2F1 and p53. Human necdin gene (NDN) is maternally imprinted and located in Prader-Willi syndrome deletion region 15q11.2-q12. We isolated an NDN homologous sequence from a human genomic DNA library. The homologous sequence is overall 83% identical with necdin cDNA sequence, and possesses a short poly(A) stretch at the 3' end and direct repeats at both ends. Expression of the homologous sequence, which lacks a 5' promoter sequence, was undetected in cultured human cell lines. We mapped this sequence to chromosome 12q14-q21.1 by fluorescence in situ hybridization. These characteristics of the NDN-homologous sequence are consistent with those of processed pseudogenes. The information about the necdin pseudogene in the human genome will be useful for genetic studies on NDN-associated neurogenic disorders.
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PMID:Characterization and chromosomal mapping of a human Necdin pseudogene. 1071 59

Induction of apoptosis seems to be a key function in maintaining normal cell growth by exerting negative controls on cell proliferation and suppressing tumorigenesis. The adenovirus E1A oncogene shows both cell cycle progression and apoptotic functions. To understand the mechanism of E1A-induced apoptosis, the apoptotic function of E1A 13S was investigated in p53-null cells. We show here that E1A is sufficient by itself to induce substantial apoptosis independent of p53 and other adenoviral genes. The apoptotic function of E1A is accompanied by processing of caspase-3 and cleavage of poly(ADP-ribose)-polymerase. Cell death is significantly blocked by the caspase inhibitor zVAD-fmk and when coexpressed with E1B19K, Bcl-2 or the retinoblastoma protein (RB). Analyses of E1A mutants indicated that the apoptotic activity of E1A correlates closely with the ability to bind the key regulators of E2F1-induced apoptosis, p300 and RB. Finally, in vivo relevance of down-modulation of p53-independent apoptosis for efficient transformation is demonstrated.
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PMID:E1A is sufficient by itself to induce apoptosis independent of p53 and other adenoviral gene products. 1071 32

Thymic negative selection is the process in which maturing thymocytes that express T-cell receptors recognizing self are eliminated by apoptotic cell death. The molecular mechanism by which this occurs is poorly understood. Notably, genes involved in cell death, even thymocyte death, such as Fas, Fas-ligand, p53, caspase-1, caspase-3, and caspase-9, and Bcl-2 have been found to not be required for normal thymic negative selection. We have demonstrated previously that E2F1-deficient mice have a defect in thymocyte apoptosis. Here we show that E2F1 is required for normal thymic negative selection. Furthermore, we observed an E2F1-dependent increase of p53 protein levels during the process of thymic clonal deletion, which suggests that E2F1 regulates activation-induced apoptosis of self-reactive thymocytes by a p53-dependent mechanism. In contrast, other apoptotic pathways operating on developing thymocytes, such as glucocorticoid-induced cell death, are not mediated by E2F1. The T lymphocytes that escape thymic negative selection migrate to the peripheral immune system but do not appear to be autoreactive, indicating that there may exist E2F1-independent mechanisms of peripheral tolerance, which protect mice from developing an autoimmune response. We expect that E2F1-deficient mice will provide a useful tool for understanding the molecular mechanism of and the immunological importance of thymic negative selection.
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PMID:A role for E2F1 in the induction of apoptosis during thymic negative selection. 1071 65

Although B-amyloid (AB) is suggested to play an important role in Alzheimer's disease, the mechanisms that control AB-evoked toxicity are unclear. We demonstrated previously that the cell cycle-related cyclin-dependent kinase 4/6/retinoblastoma protein pathway is required for AB-mediated death. However, the downstream target(s) of this pathway are unknown. We show here that neurons lacking E2F1, a transcription factor regulated by the retinoblastoma protein, are significantly protected from death evoked by AB. Moreover, p53 deficiency does not protect neurons from death, indicating that E2F1-mediated death occurs independently of p53. Neurons protected by E2F1 deficiency have reduced Bax-dependent caspase 3-like activity. However, protection afforded by E2F1, Bax, or caspase 3 deficiency is transient. In the case of E2F1, but not with Bax or caspase 3 deficiency, delayed death is accompanied by DEVD-AFC cleavage activity. Taken together, these results demonstrate the required role of E2F1, Bax, and caspase 3 in AB evoked death, but also suggest the participation of elements independent of these apoptosis regulators.
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PMID:E2F1 mediates death of B-amyloid-treated cortical neurons in a manner independent of p53 and dependent on Bax and caspase 3. 1076 69

Necdin, a growth suppressor expressed predominantly in postmitotic neurons, interacts with viral oncoproteins and cellular transcription factors E2F1 and p53. In search of other cellular targets of necdin, we screened cDNA libraries from neurally differentiated murine embryonal carcinoma P19 cells and adult rat brain by the yeast two-hybrid assay. We isolated cDNAs encoding partial sequences of mouse NEFA and rat nucleobindin (CALNUC), which are Ca(2+)-binding proteins possessing similar domain structures. Necdin interacted with NEFA via a domain encompassing two EF hand motifs, which had Ca(2+) binding activity as determined by (45)Ca(2+) overlay. NEFA was widely distributed in mouse organs, whereas necdin was expressed predominantly in the brain and skeletal muscle. In mouse brain in vivo, NEFA was localized in neuronal perikarya and dendrites. By immunoelectron microscopy, NEFA was localized to the cisternae of the endoplasmic reticulum and nuclear envelope in brain neurons. NEFA-green fluorescent protein (GFP) fusion protein expressed in neuroblastoma N1E-115 cells was retained in the cytoplasm and partly secreted into the culture medium. Necdin enhanced the cytoplasmic retention of NEFA-GFP and potentiated the effect of NEFA-GFP on caffeine-evoked elevation of cytosolic Ca(2+) levels. Thus, necdin and NEFA might be involved in Ca(2+) homeostasis in neuronal cytoplasm.
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PMID:The postmitotic growth suppressor necdin interacts with a calcium-binding protein (NEFA) in neuronal cytoplasm. 1091 98

Neuronal degeneration associated with human immunodeficiency virus encephalitis has been attributed to neurotoxicity of signaling molecules secreted by activated, infected macrophages. We hypothesized that the barrage of signals present in the extracellular milieu of human immunodeficiency virus-infiltrated brain causes inappropriate activation of neuronal cell-cycle machinery. We examined the presence of three members of the cell-cycle control machinery: pRb, E2F1, and p53 in the simian immunodeficiency virus encephalitis (SIVE) model. Compared to noninfected and simian immunodeficiency virus-infected, nonencephalitic controls, we observed increased protein expression of E2F1 and p53 and aberrant cellular localization of E2F1 and pRb. In SIVE, E2F1 was abundant in the cytoplasm of neurons in both neurons and astrocytes proximal to SIVE pathology in the basal ganglia. pRb staining was nuclear and cytoplasmic in cortical neurons of SIVE cases. Antibodies to phosphorylated pRb also labeled the cytoplasm of cortical neurons. These data suggest that in SIVE, cell signaling results in phosphorylation of pRb which may result in subsequent alteration in E2F1 activity. As increased E2F1 and p53 activities have been linked to cell death, these data suggest that the neurodegeneration in SIVE could in part be because of changes in expression and activity of cell-cycle machinery.
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PMID:Induction of cell-cycle regulators in simian immunodeficiency virus encephalitis. 1093 53

Necdin is a 325-amino-acid residue protein encoded by a cDNA clone isolated from neurally differentiated embryonal carcinoma cells. Ectopic expression of necdin induces growth arrest of proliferative cells. Necdin binds to major transcription factors E2F1 and p53, suggesting that necdin exerts its functions through the interactions with these cell-cycle-regulating factors. However, information about precise localization of endogenous necdin protein is currently lacking. A rabbit polyclonal antibody was raised against a bacterially expressed recombinant protein of necdin (amino acids 83-325). Immunoblot analysis revealed that necdin protein was expressed almost exclusively in the brain of adult mice. A relative molecular mass of endogenous necdin was estimated at approximately 43,000. In developing mouse brain, necdin was most abundant during fetal and neonatal periods. Necdin was highly enriched in the cytoplasm of hypothalamic neurons in fetal and adult mice. The subcellular fractionation analysis revealed that necdin was concentrated in the cytosol fraction of brain cells. These results suggest that endogenous necdin protein is localized predominantly in the cytoplasm of differentiated neurons and moves into the nucleus under specific conditions.
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PMID:Cellular and subcellular localization of necdin in fetal and adult mouse brain. 1096 53


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