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)

P53 is of key importance for the protection of an organism against carcinogenesis. P53 performs this function by the regulation of several cellular processes, the most important of which are apoptosis and cell-cycle progression. P53 controls these processes most likely through the transcriptional regulation of target genes, such as those for p21waf1 and bax. Since p53 is involved in the regulation of these distinct processes, the protein should be able to respond quickly to environmental changes. P53 is a phosphoprotein phosphorylated on multiple sites by a variety of kinases. The two main phosphorylation domains are the N and the C terminus. The N-terminal part contains the transcription-regulatory domain of p53, while the C-terminal domain controls the specific DNA binding by p53. Here we present an overview of the kinases known to phosphorylate p53 and the effects of phosphorylation on biochemical and biological functions. The picture that emerges shows that phosphorylation of p53 on specific sites can modulate the activity of the protein, either by affecting its abundance, the affinity for its DNA-consensus sequence or the activity of the transcription-activation domain. Furthermore, the kinases involved are downstream targets of different inducers, such as DNA-damage/stress inducers and mitogens, giving the cell the opportunity to respond to distinct extracellular stimuli via modulation of p53 activity.
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PMID:How phosphorylation regulates the activity of p53. 891 92

Several cellular polypeptides critical for growth regulation interact with DNA tumor virus oncoproteins. p400 is a cellular protein which binds to the adenovirus E1A oncoprotein(s). The biological function of p400 is not yet known, but it is structurally and immunologically closely related to p300 and CREB-binding protein, two known E1A-binding transcription adapters. Like p300, p400 is a phosphoprotein that binds to the simian virus 40 large tumor antigen (T). In anti-T coimmunoprecipitation experiments, staggered deletions spanning the amino-terminal 250 amino acids of T did not abrogate T binding to either p400 or p300. A T species composed of residues 251 to 708 bound both p400 and p300, while a T species defective in p53 binding was unable to bind either detectably. Anti-p53 immunoprecipitates prepared from cells containing wild-type T also contained p400 and p300. Hence, both p400 and p300 can bind (directly or indirectly) to a carboxyl-terminal fragment of T which contains its p53 binding domain. Since the p53 binding domain of T contributes to its immortalizing and transforming activities, T-p400 and/or T-p300 interactions may participate in these functions.
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PMID:p300 family members associate with the carboxyl terminus of simian virus 40 large tumor antigen. 898 31

A cellular phosphoprotein that binds to and inactivates p53 has recently been identified as a product of the oncogene MDM2. Amplification of the MDM2 gene was found in more than a third of sarcomas and in a subset of malignant gliomas. Despite the absence of amplification, the MDM2 gene was overexpressed in some types of leukemias and lymphomas. Overexpression was significantly more frequent in the low-grade type of B-cell non-Hodgkin's lymphoma (B-NHL) than in the intermediate/high grade types of lymphoma and the overexpression was also significantly more frequent in the advanced rather than the earlier stages of B-cell chronic lymphocytic leukemia (B-CLL) and B-NHL. This suggests that MDM2 could play a role, via the p53 pathway, in tumorigenicity and/or in disease progression in some hematological malignancies. However, in the light of our findings that, in a few cases, both the overexpression of MDM2 and mutant-type p53 was seen, it is possible that MDM2 overexpression may also promote neoplastic growth by mechanisms other than inactivation of the p53 protein.
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PMID:Overexpression of the MDM2 oncogene in leukemia and lymphoma. 917 3

Alterations of the p53 protein, which is a 53 kD phosphoprotein and gene product of the p53 gene, has been found to play a major role in the genesis of a variety of human malignancies including tumors of the central nervous system. We investigated 50 tumor specimens from primary central nervous system neoplasms. Tissue samples were screened for mutations by the single-strand conformation polymorphism method and detected mutations were sequenced. All tissue specimens were stained immunohistochemically for p53 protein, which when altered accumulates in the nucleus due to prolonged half-life. Mutations were found in six cases, including one pilocytic astrocytoma World Health Organization (WHO) grade I, two astrocytomas WHO grade II, two anaplastic astrocytomas WHO grade III, and one primitive neuroectodermal tumor (PNET). In terms of relative frequency mutations were found mostly in the group of anaplastic astrocytomas WHO grade III. Interestingly, no mutations were found in the group of investigated glioblastomas. P53 immunopositivity did not correlated with the mutations found, whereas the staining index was significantly higher in the cases with detected mutations than in those without. When p53 alterations is seen as an indicator for different pathogenic pathways in glioma formation, this study gives evidence for a difference between anaplastic astrocytoma and glioblastoma. However, since there was a great overlap in p53 immunopositivity and p53 mutation in tumors of different WHO grades and entities, it seems that p53 will not act as a marker molecule neither for tumor entities nor for tumor malignancy.
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PMID:p53 mutation and protein alteration in 50 gliomas. Retrospective study by DNA-sequencing techniques and immunohistochemistry. 922 41

The p53 tumor suppressor gene encodes a phosphoprotein which when overexpressed can induce growth arrest at the G1 and G2/M phases of the cell cycle, promote differentiation and apoptosis. This paper demonstrates that p53 can associate with trk tyrosine kinase. Expression of a murine temperature-sensitive (ts) p53 mutant in PC12 cells overexpressing trk (a model system to analyse cellular differentiation and signal transduction induced by NGF) induces morphological changes in the absence of NGF stimulation at 32 degrees C but not at 37 degrees C. In cells differentiated by p53, trk, but not EGFr, was hyperphosphorylated on tyrosine. Furthermore trk was not phosphorylated when expressed in Saos-2 cells (human osteosarcoma cells that lack expression of both endogenous trk and p53) at either temperature. However, transfection of ts p53 into these cells induces trk phosphorylation at 32 degrees C in the absence of NGF stimulation. Association of trk and p53 can be detected in NIH3T3 and PC12 cells co-expressing trk and the ts p53 mutant, in NIH3T3 and PC12 cells transfected with trk alone, and in untransfected PC12 cells, showing that overexpressed and/or endogenous trk associates with endogenous, low levels of p53. These data suggest a novel function for p53 which involves the stimulation of signal transduction pathways (mediating morphological properties of cells), possibly through association with and hyperphosphorylation of trk.
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PMID:P53 associates with trk tyrosine kinase. 923 59

Human tumor suppressor protein p53 is a 393-amino acid phosphoprotein that enhances transcription in response to DNA damage from several genes that regulate cell cycle progression. The tetrameric state of p53 is critical to wild-type function; the p53 tetramerization element is located in the C-terminal region of the protein. This region is phosphorylated at several evolutionarily conserved serines, suggesting that phosphorylation may be an important regulator of p53 function. In order to determine the effect of phosphorylation on tetramer formation, we synthesized phosphopeptides corresponding to p53(Ser303-Asp393) with phosphate incorporated at Ser315, Ser378, or Ser392, and at both Ser315 and Ser392. Equilibrium ultracentrifugation analysis showed that phosphorylation at Ser392 increased the association constant for tetramer formation nearly ten-fold. By itself, phosphorylation at Ser315 or Ser378 had little effect on tetramer formation, but Ser315 largely reversed the effect of phosphorylation at Ser392. Analysis by calorimetry suggests that phosphorylation may influence subunit affinity by an enthalpy driven process.
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PMID:Effect of phosphorylation on tetramerization of the tumor suppressor protein p53. 924 43

Tumor suppressor protein p53 is a tetrameric phosphoprotein that activates transcription from several cell cycle regulating genes in response to DNA damage. Tetramer formation is critical to p53's ability to activate transcription; however, posttranslational modifications and protein stabilization also contribute to p53's ability to activate transcription. To determine if phosphorylation affects tetramer formation, we synthesized phosphopeptides corresponding to residues 303-393 of human p53, which includes the domain responsible for tetramer formation. Phosphate was chemically incorporated at Ser315, Ser378, or Ser392 and also at both Ser315 and Ser392. Equilibrium ultracentrifugal analyses showed that phosphorylation at Ser392 increased the association constant for reversible tetramer formation nearly 10-fold. Phosphorylation of either Ser315 or Ser378 had little effect on tetramer formation, but phosphorylation of Ser315 largely reversed the effect of phosphorylation at Ser392. Analyses by calorimetry demonstrated that phosphorylation may influence subunit affinity (and, in turn, DNA binding) by an enthalpy-driven process, possibly between the C-terminal residues and the region immediately adjacent to Ser315. The Kd for the tetramer-monomer transition of the unphosphorylated p53 C-terminal domain was determined to be approximately 1-10 microM. Thus, in normal, undamaged cells p53 may be largely monomeric. Enhancement of tetramer formation through phosphorylation of Ser392, coupled with a DNA-damage-induced increase in its nuclear concentration, could provide a switch that activates p53 as a transcription factor in response to DNA damage.
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PMID:Phosphorylation of serine 392 stabilizes the tetramer formation of tumor suppressor protein p53. 925 8

Gene mutations provide valuable clues to cellular metabolism. In humans such insights come mainly from genetic disorders. Ataxia-telangiectasia (A-T) and Nijmegen breakage syndrome (NBS) are two distinct but closely related, single gene disorders that highlight a complex junction of several signal transduction pathways. These pathways appear to control defense mechanisms against specific types of damage to cellular macromolecules, and probably regulate the processing of certain types of DNA damage or normal intermediates of DNA metabolism. A-T is characterized primarily by cerebellar degeneration, immunodeficiency, genome instability, clinical radiosensitivity, and cancer predisposition. NBS shares all these features except cerebellar deterioration. The cellular phenotypes of A-T and NBS are almost indistinguishable, however, and include chromosomal instability, radiosensitivity, and defects in cell cycle checkpoints normally induced by ionizing radiation. The recent identification of the gene responsible for A-T, ATM, has revealed its product to be a large, constitutively expressed phosphoprotein with a carboxy-terminal region similar to the catalytic domain of phosphatidylinositol 3-kinases (PI 3-kinases). ATM is a member of a family of proteins identified in various organisms, which share the PI 3-kinase domain and are involved in regulation of cell cycle progression and response to genotoxic agents. Some of these proteins, most notably the DNA-dependent protein kinase, have an associated protein kinase activity, and preliminary data indicate this activity in ATM as well. Mutations in A-T patients are null alleles that truncate or destabilize the ATM protein. Atm-deficient mice recapitulate the human phenotype with slower nervous-system degeneration. Two ATM interactors, c-Abl and p53, underscore its role in cellular responses to genotoxic stress. The complexity of ATM's structure and mode of action make it a paradigm of multifaceted signal transduction proteins involved in many physiological pathways via multiple protein-protein interactions. The as yet unknown NBS protein may be a component in an ATM-based complex, with a key role in sensing and processing specific DNA damage or intermediates and signaling their presence to the cell cycle machinery.
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PMID:Ataxia-telangiectasia and the Nijmegen breakage syndrome: related disorders but genes apart. 944 10

Mts1 is a metastasis-associated gene of the S-100 gene family and codes for a Ca2+-binding protein. It is highly expressed in murine and human cancers of high invasive and metastatic potential. Recent work has shown that the mts1 protein might be involved in cell cycle regulation. An upregulation of its expression drives cells into the S phase, together with an enhanced expression of p53 phosphoprotein, which has led to the suggestion that mtsl protein might be sequestering p53 thereby abrogating the G1-S checkpoint control normally exerted by p53. Preliminary studies showed that expression of mts1 is downregulated by hyperthermia. We present evidence that in murine BL6 melanoma cells and human HUT cells that hyperthermia downregulates the mts1 gene. It is also downregulated in heat-resistant variants of the B16 melanoma and HUT cells. In parallel, there is a decrease in the size of the S phase fraction and an increase in the doubling time of cells. Cell subjected to hyperthermia show an 2- to 3.5-fold increase in the expression of HSP28 which has been shown to possess a proliferation inhibitory action. It is postulated that a complete regulatory loop involving mtsl, p53, and HSP28 might be involved in cell proliferation.
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PMID:Heat shock modulates the expression of the metastasis associated gene MTS1 and proliferation of murine and human cancer cells. 946 17

Although most papillary thyroid microcarcinomas (PMCs) are of little clinical significance, patients with PMCs occasionally have an unfavorable outcome, especially when they present with bulky nodal metastasis or distant metastasis. We have attempted to identify "high-risk" PMCs by evaluating clinical, pathologic, and immunohistochemical prognostic factors. Among 190 patients with a PMC, 156 without clinically apparent nodal metastasis had a benign course. The remaining 34 patients, who presented with cervical lymphadenopathy of at least 1 cm, were studied. Three of the four patients who developed distant metastasis died of the disease, and the other died of local recurrence. All patients who developed distant metastasis or died of the disease had both nodal metastasis of at least 3 cm and a nonencapsulated type of primary lesion. All patients who developed distant metastasis showed both extracapsular extension of the metastatic lesions in lymph nodes and positive staining for transforming growth factor-beta3 (TGFbeta3) (a potent growth inhibitor) in the primary lesion. The Ki-67 (an indicator of cell proliferation) labeling indices in the primary and metastatic nodal lesions of patients who died of cancer were significantly higher than those of the others with nonfatal disease. None of the patients showed P53 (nuclear tumor-suppressor phosphoprotein) overexpression. In conclusion, patients with PMC who have both 3 cm or larger lymphadenopathy and a nonencapsulated type of primary lesion may be regarded as high-risk patients. Immunohistologic positivity for Ki-67 and TGFbeta3 in cancer cells is a potential indicator of aggressively malignant PMC.
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PMID:Clinicopathologic and immunohistochemical studies of papillary thyroid microcarcinoma presenting with cervical lymphadenopathy. 960 90


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