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)

In the present study, we employed 2-DE to characterize the effect of the acute promyelocytic leukemia (APL)-specific PML-RARalpha fusion protein on the proteome. Differentially expressed proteins, a number of which are related to the cell cycle function, including oncoprotein18 (OP18), heat shock protein70, glucose-regulated protein75, and peptidyl-prolyl isomerase, were identified by MS. Subsequent bioinformatic pathway discovery revealed an integrated network constituting SMARCB1, MYC, and TP53-regulated pathways. The data from the DNA microarray and proteomic experiments demonstrated the correlation between the translocation and higher expression of OP18 at mRNA and protein levels. Transient cotransfection assay revealed that PML-RARalpha is a potent activator of OP18 promoter and this transcriptional activation is retinoic acid sensitive. PML-RARalpha induction also leads to decreased phosphorylation on Ser63 residue of OP18, which is okadaic acid sensitive suggesting the involvement of a phosphatase pathway. Overexpression of a constitutively phosphorylated Ser63 mutant of OP18 in PML-RARalpha expressing APL patient, PR9, and NB4 cells led to a G2/M-phase arrest in contrast to a phosphorylation-deficient Ser63 mutant and untransfected control. Taken together, our results demonstrate the significance of decreased Ser63 phosphorylation of OP18 in PML-RARalpha-mediated effects on cell cycle.
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PMID:Proteomic analysis of acute promyelocytic leukemia: PML-RARalpha leads to decreased phosphorylation of OP18 at serine 63. 1700 4

Gene expression is mostly controlled at the level of the transcription initiation. The transcription control regions of protein-encoding genes include: the core promoter, where RNA polymerase II binds, the proximal and distal promoter, responsible for gene expression regulation, and the enhancers and silencers. Chromatin represents an additional level of regulation of gene expression. The switching between inactive and active chromatin is closely related to the activity of histone-modifying enzymes and chromatin-remodelling complexes. Transcriptional activation of a gene requires the binding of specific transcription factors to regulatory DNA elements, the opening of the chromatin, the binding of Mediator, and the assembly of the preinitiation complex with RNA polymerase and RNA synthesis initiation. Transcription factors ultimately transduce the proliferation signals elicited by growth factors. Moreover, many human oncogenes encode for transcription factors, and some of them are prevalent in particular neoplasias (e.g., MYC, MLL, PML-RARa). Also, some of the most prominent tumor suppressors (e.g. p53) are transcription factors.
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PMID:Gene expression regulation and cancer. 1713 65

The promyelocytic leukaemia gene (Pml) is a tumor suppressor identified in acute promyelocytic leukaemia (APL), where it is fused to RAR alpha gene as a result of the chromosomal translocation t(15;17). Pml encodes both nuclear and cytoplasmic isoforms. While nuclear PML has been intensively investigated, cytoplasmic PML proteins are less characterized. PML nuclear isoforms (nPML) are the essential components of subnuclear structures referred to as PML nuclear bodies (PML-NB). In response to cellular insults such as DNA damage and oncogenic activation, nPML modulates p53 activity through CBP-mediated acetylation and activates its pro-apoptotic and growth suppressive functions. Two missense mutations resulting in truncated PML cytoplasmic proteins (Mut PML) have been identified in aggressive APL cases. Here we report that cytoplasmic PML is able to induce the relocation of nPML to the cytoplasm, thus reducing the number of PML-NBs. Remarkably, Mut PML inhibits p53 transcriptional, growth suppressive, and apoptotic functions, thus suggesting that cytoplasmic expression of PML has an impact on survival through inhibition of nuclear PML. Overall our findings shed new light on the role of PML cytoplasmic proteins in the regulation of p53.
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PMID:A cytoplasmic PML mutant inhibits p53 function. 1717 28

This study examined the role of Daxx in ischemic stress. Upon ischemic stress, nuclear export of Daxx to the cytoplasm was observed in primary myocytes as well as in various cell lines. Daxx silencing using siRNAs was detrimental in tethering PML-nuclear body (PML-NB) constituents together. Overexpression of Daxx (W621A) caused nuclear export of p53 independently of PML and promoted ischemic cell death via activation of JNK. Conversely, overexpression of Daxx (S667A) prevented dissociation of PML-NB constituents and protected cells from ischemic death. Collectively, our results demonstrate that the subcellular localization of Daxx determines its role in ischemic cell death.
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PMID:Subcellular localization of Daxx determines its opposing functions in ischemic cell death. 1728 31

Chk2 is a protein kinase involved in the ATM-dependent checkpoint pathway (http://discover.nci.nih.gov/mim). This pathway is activated by genomic instability and DNA damage and results in either cell cycle arrest, to allow DNA repair to occur, or cell death (apoptosis). Chk2 is activated by ATM-mediated phosphorylation and autophosphorylation and in turn phosphorylates its downstream targets (Cdc25A, Cdc25C, BRCA1, p53, Hdmx, E2F1, PP2A, and PML). Inhibition of Chk2 has been proposed to sensitize p53-deficient cells as well as protect normal tissue after exposure to DNA-damaging agents. We have developed a drug-screening program for specific Chk2 inhibitors using a fluorescence polarization assay, immobilized metal ion affinity-based fluorescence polarization (IMAP). This assay detects the degree of phosphorylation of a fluorescently linked substrate by Chk2. From a screen of over 100,000 compounds from the NCI Developmental Therapeutics Program, we identified a bis-guanylhydrazone [4,4'-diacetyldiphenylureabis(guanylhydrazone); NSC 109555] as a lead compound. In vitro data show the specific inhibition of Chk2 kinase activity by NSC 109555 using in vitro kinase assays and kinase-profiling experiments. NSC 109555 was shown to be a competitive inhibitor of Chk2 with respect to ATP, which was supported by docking of NSC 109555 into the ATP binding pocket of the Chk2 catalytic domain. The potency of NSC 109555 was comparable with that of other known Chk2 inhibitors, such as debromohymenialdisine and 2-arylbenzimidazole. These data define a novel chemotype for the development of potent and selective inhibitors of Chk2. This class of drugs may ultimately be useful in combination with current DNA-damaging agents used in the clinic.
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PMID:Identification of a Bis-guanylhydrazone [4,4'-Diacetyldiphenylurea-bis(guanylhydrazone); NSC 109555] as a novel chemotype for inhibition of Chk2 kinase. 1761 32

Cellular senescence is an irreversible proliferation arrest of primary cells and an important tumor suppression process. Senescence is often characterized by domains of facultative heterochromatin, called senescence-associated heterochromatin foci (SAHF), which repress expression of proliferation-promoting genes. Formation of SAHF is driven by a complex of histone chaperones, HIRA and ASF1a, and depends upon prior localization of HIRA to PML nuclear bodies. However, how the SAHF assembly pathway is activated in senescent cells is not known. Here we show that expression of the canonical Wnt2 ligand and downstream canonical Wnt signals are repressed in senescent human cells. Repression of Wnt2 occurs early in senescence and independently of the pRB and p53 tumor suppressor proteins and drives relocalization of HIRA to PML bodies, formation of SAHF and senescence, likely through GSK3beta-mediated phosphorylation of HIRA. These results have major implications for our understanding of both Wnt signaling and senescence in tissue homeostasis and cancer progression.
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PMID:Downregulation of Wnt signaling is a trigger for formation of facultative heterochromatin and onset of cell senescence in primary human cells. 1764 69

Daxx plays a major role in several important signaling pathways including transcription and cell death. It has been postulated that Daxx regulates both events from the nucleus; however, the mechanism by which Daxx is localized in the nucleus remains obscure. Here we show that nuclear localization of Daxx is controlled by two independent signals and importin 3. Domain analysis reveals that Daxx contains two separate nuclear localizing domains. Site-directed mutagenesis reveals that the basic aa sequence RLKRK at residues 227-231 (NLS1) is responsible for nuclear localization of N-terminal domain, while aa sequence KKSRKEKK at residues 630-637 (NLS2) is responsible for nuclear localization of the C-terminal domain. Mutations of a NLS consensus sequence RKKRR at residues 391-395 and several other basic aa clusters have no effect on Daxx nuclear localization. In full-length Daxx, NLS1 contributes partially to nuclear localization, while NLS2 plays a major role. Markedly, it is essential to disrupt both NLS1 and NLS2 in order to completely block nuclear localization of the full-length protein and to prevent its association with PML nuclear bodies. Furthermore, Daxx interacts selectively with importin alpha3 through its NLS1 and NLS2 sequences. Conversely, importin alpha3 utilizes two NLS-binding sites for Daxx interaction, suggesting that the importin/mediates nuclear import of Daxx. Finally, we show that nuclear localization of Daxx is essential for its transcriptional effects on GR and p53. Together, these data unveil a molecular mechanism that controls nuclear localization of Daxx and support a nuclear role of Daxx in transcriptional regulation.
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PMID:Daxx contains two nuclear localization signals and interacts with importin alpha3. 1766 48

Promyelocytic leukaemia protein nuclear bodies (PML-NBs) are nuclear structures whose function is still poorly understood. They are implicated in various biological functions, such as viral infection, cellular transformation, innate immunity and growth control, and they might be dynamic hubs sensing stress and DNA damage. Data from PML(-/-) mice suggest that PML-NBs are involved in apoptosis via caspase-independent mechanisms, probably involving p53-dependent and independent pathways. However, the recently demonstrated co-localization of caspase-2 within the PML-NB nuclear structures presents a new paradigm for nuclear cell death. Here, we show that these nuclear structures have a protein known as SP100 that could contain a caspase recruitment domain (CARD). If verified experimentally, this discovery will suggest a mechanism by which caspase-2 could be recruited into the complex and ultimately lead to apoptosis.
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PMID:Are promyelocytic leukaemia protein nuclear bodies a scaffold for caspase-2 programmed cell death? 1769 89

Alternative lengthening of telomere (ALT) tumors maintain telomeres by a telomerase-independent mechanism and are characterized by a nuclear structure called the ALT-associated PML body (APB). TRF2 is a component of a telomeric DNA/protein complex called shelterin. However, TRF2 function in ALT cells remains elusive. In telomerase-positive tumor cells, TRF2 inactivation results in telomere de-protection, activation of ATM, and consequent induction of p53-dependent apoptosis. We show that in ALT cells this sequence of events is different. First, TRF2 inactivation/silencing does not induce cell death in p53-proficient ALT cells, but rather triggers cellular senescence. Second, ATM is constitutively activated in ALT cells and colocalizes with TRF2 into APBs. However, it is only following TRF2 silencing that the ATM target p53 is activated. In this context, PML is indispensable for p53-dependent p21 induction. Finally, we find a substantial loss of telomeric DNA upon stable TRF2 knockdown in ALT cells. Overall, we provide insight into the functional consequences of shelterin alterations in ALT cells.
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PMID:Lack of TRF2 in ALT cells causes PML-dependent p53 activation and loss of telomeric DNA. 1805 7

Hes6 is a basic helix-loop-helix transcription factor that functions in the differentiation of pluripotent progenitor cells and during tumorigenesis. However, the molecular mechanism for its function is largely unknown. Here we show that Hes6 is a component of the promyelocytic leukemia nuclear body (PML-NB) complex in the nuclei and that Hes6 inhibits cell proliferation through induction of p21 cyclin-dependent kinase inhibitor. We further show that Hes6 directly interacts with CREB-binding protein (CBP), one of the key components of PML-NB, via its basic domain. This association is critical for p21 induction through multiple mechanisms, including chromatin remodeling and p53 acetylation. Taken together, these results suggest that the Hes6-CBP complex in PML-NB may influence the proliferation of cells via p53-dependent and -independent pathways.
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PMID:Hes6 controls cell proliferation via interaction with cAMP-response element-binding protein-binding protein in the promyelocytic leukemia nuclear body. 1816 Apr


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