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)

Post-translational modifications control the physiological activity of the signal transducer and activator of transcription STAT1. While phosphorylation at tyrosine Y701 is a prerequisite for STAT1 dimerization, its SUMOylation represses the transcriptional activity. Recently, we have demonstrated that SUMOylation at lysine K703 inhibits the phosphorylation of nearby localized Y701 of STAT1. Here, we analysed the influence of phosphorylation of Y701 on SUMOylation of K703 in vivo. For that reason, an Ubc9/substrate dimerization-dependent SUMOylation (USDDS) system was developed, which consists of fusions of the SUMOylation substrate and of the SUMO-conjugating enzyme Ubc9 to the chemically activatable heterodimerization domains FKBP and FRB, respectively. When FKBP fusion proteins of STAT1, p53, CRSP9, FOS, CSNK2B, HES1, TCF21 and MYF6 are coexpressed with Ubc9-FRB, treatment of HEK293 cells with the rapamycin-related dimerizer compound AP21967 induces SUMOylation of these proteins in vivo. For STAT1-FKBP and p53-FKBP we show that this SUMOylation takes place at their specific SUMOylation sites in vivo. Using USDDS, we then demonstrate that STAT1 phosphorylation at Y701 induced by interferon-beta treatment inhibits SUMOylation of K703 in vivo. Thus, pY701 and SUMO-K703 of STAT1 represent mutually exclusive modifications, which prevent signal integration at this molecule and probably ensure the existence of differentially modified subpopulations of STAT1 necessary for its regulated nuclear cytoplasmic activation/inactivation cycle.
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PMID:Mutually exclusive STAT1 modifications identified by Ubc9/substrate dimerization-dependent SUMOylation. 1917 62

p53 and its cousins p63 and p73 are critical regulators of the genotoxic stress response in mammalian cells. Their activity is controlled by an intricate network of post-translational modifications. The ubiquitin-like SUMO system targets all three family members and modulates their transcriptional activity, stability or subcellular trafficking. While the SUMO system appears to primarily exert a negative regulatory function on p73 and p63, both activating and repressing activities have been reported on p53. Here we will give a synopsis of the multifaceted effects of SUMO on p53 family members.
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PMID:Regulation of p53 family members by the ubiquitin-like SUMO system. 1921 14

Polo-like kinase 1 (Plk1) overexpression is associated with tumorigenesis by an unknown mechanism. Likewise, Plk1 was suggested to act as a negative regulator of tumor suppressor p53, but the mechanism remains to be determined. Herein, we have identified topoisomerase I-binding protein (Topors), a p53-binding protein, as a Plk1 target. We show that Plk1 phosphorylates Topors on Ser(718) in vivo. Significantly, expression of a Plk1-unphosphorylatable Topors mutant (S718A) leads to a dramatic accumulation of p53 through inhibition of p53 degradation. Topors is an ubiquitin and small ubiquitin-like modifier ubiquitin-protein isopeptide ligase (SUMO E3) ligase. Plk1-mediated phosphorylation of Topors inhibits Topors-mediated sumoylation of p53, whereas p53 ubiquitination is enhanced, leading to p53 degradation. These results demonstrate that Plk1 modulates Topors activity in suppressing p53 function and identify a likely mechanism for the tumorigenic potential of Plk1.
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PMID:Plk1-mediated phosphorylation of Topors regulates p53 stability. 1947 92

The phytocannabinoid Delta(9)-Tetrahydrocannabinol (Delta(9)-THC), the main psychoactive cannabinoid in cannabis, activates a number of signalling cascades including p53. This study examines the role of Delta(9)-THC in regulating the p53 post-translational modifier proteins, Murine double minute (Mdm2) and Small Ubquitin-like MOdifier protein 1 (SUMO-1) in cortical neurons. Delta(9)-THC increased both Mdm2 and SUMO-1 protein expression and induced the deSUMOylation of p53 in a cannabinoid receptor type 1 (CB(1))-receptor dependent manner. We demonstrate that Delta(9)-THC decreased the SUMOylation of the CB(1) receptor. The data reveal a novel role for cannabinoid receptor activation in modulating the SUMO regulatory system.
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PMID:Delta(9)-tetrahydrocannabinol regulates the p53 post-translational modifiers Murine double minute 2 and the Small Ubiquitin MOdifier protein in the rat brain. 1981 40

Coxsackievirus B5 (CVB5), a human enterovirus of the family Picornaviridae, is a frequent cause of acute and chronic human diseases. The pathogenesis of enteroviral infections is not completely understood, and the fate of the CVB5-infected cell has a pivotal role in this process. We have investigated the CVB5-induced apoptosis of HeLa cells and found that it happens by the intrinsic pathway by a mechanism dependent on the ubiquitin-proteasome system, associated with nuclear aggregation of p53. Striking redistribution of both SUMO and UBC9 was noted at 4 h post-infection, simultaneously with a reduction in the levels of the ubiquitin-ligase HDM2. Taken together, these results suggest that CVB5 infection of HeLa cells elicit the intrinsic pathway of apoptosis by MDM2 degradation and p53 activation, destabilizing protein sumoylation, by a mechanism that is dependent on a functional ubiquitin-proteasome system.
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PMID:Coxsackievirus B5 induced apoptosis of HeLa cells: effects on p53 and SUMO. 1990 94

The p68 (DDX5) and p72 (DDX17) proteins are members of the DEAD-box (DDX) family of RNA helicases. We show that both p68 and p72 are overexpressed in breast tumors. Bioinformatical analysis revealed that the SUMO pathway is upregulated in breast tumors and that both p68 and p72 contain one consensus sumoylation site, implicating that sumoylation of p68 and p72 increases during breast tumorigenesis and potentially contributes to their overexpression. We determined that p68 and p72 are indeed sumoylated at a single, homologous site. Importantly, sumoylation significantly increased the stability of p68 and p72. In contrast to p72 and consistent with an approximately 3-fold lesser half-life, p68 was found to be polyubiquitylated, and mutation of the sumoylation site increased polyubiquitylation, suggesting that sumoylation increases p68 half-life by reducing proteasomal degradation. Moreover, whereas p68 robustly coactivated transcription from an estrogen response element, its sumoylation mutant showed a drastically reduced coactivation potential. In contrast, the p68 sumoylation status did not affect the ability to enhance p53-mediated MDM2 transcription. On the contrary, preventing sumoylation of p72 caused an increase in its ability to transactivate both estrogen receptor and p53. Furthermore, sumoylation promoted the interaction of p68 and p72 with histone deacetylase 1 but had no effect on binding to histone deacetylases 2 and 3, the coactivator p300, or estrogen receptor and also did not affect homo/heterodimerization of p68/p72. In conclusion, sumoylation exerts pleiotropic effects on p68/p72, which may have important implications in breast cancer by modulating estrogen receptor and p53 activity.
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PMID:Sumoylation of p68 and p72 RNA helicases affects protein stability and transactivation potential. 1999 69

Sumoylation has emerged as a major post-translational modification of cellular proteins, affecting a variety of cellular processes. Viruses have exploited the sumoylation pathway to advance their own replication by evolving several ways to perturb the host sumoylation apparatus. However, there has been no report of virally encoded enzymes directly involved in catalyzing the sumoylation reaction. Here, we report that the K-bZIP protein encoded by Kaposi's sarcoma-associated herpesvirus (KSHV) is a SUMO E3 ligase with specificity toward SUMO2/3. K-bZIP is a nuclear factor that functions to modulate viral gene expression and to prolong the G1 phase, allowing viral transcription and translation to proceed at the early stage of infection. In addition to functioning as a transcriptional factor, we show that K-bZIP carries a SIM (SUMO-interacting motif), which specifically binds to SUMO-2/3 but not SUMO-1. K-bZIP catalyzes its own SUMO modification as well as that of its interacting partners such as the cellular tumor suppressor proteins p53 and Rb, both in vitro and in vivo. This reaction depends on an intact SIM. Sumoylation of p53 leads to its activation and K-bZIP is recruited to several p53 target chromatin sites in a SIM-dependent manner. In addition to the identification of a viral SUMO-2/3 E3 ligase, our results provide additional insights into the mechanisms whereby K-bZIP induces cell cycle arrest.
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PMID:Kaposi's sarcoma-associated herpesvirus (KSHV) encodes a SUMO E3 ligase that is SIM-dependent and SUMO-2/3-specific. 2003 35

Synergy between transcription factors operating together on complex promoters is a key aspect of gene activation. The ability of specific factors to synergize is restricted by sumoylation (synergy control, SC). Focusing on the haematopoietic transcription factor c-Myb, we found evidence for a strong SC linked to SUMO-conjugation in its negative regulatory domain (NRD), while AMV v-Myb has escaped this control. Mechanistic studies revealed a SUMO-dependent switch in the function of NRD. When NRD is sumoylated, the activity of c-Myb is reduced. When sumoylation is abolished, NRD switches into being activating, providing the factor with a second activation function (AF). Thus, c-Myb harbours two AFs, one that is constitutively active and one in the NRD being SUMO-regulated (SRAF). This double AF augments c-Myb synergy at compound natural promoters. A similar SUMO-dependent switch was observed in the regulatory domains of Sp3 and p53. We show that the change in synergy behaviour correlates with a SUMO-dependent differential recruitment of p300 and a corresponding local change in histone H3 and H4 acetylation. We therefore propose a general model for SUMO-mediated SC, where SUMO controls synergy by determining the number and strength of AFs associated with a promoter leading to differential chromatin signatures.
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PMID:A SUMO-regulated activation function controls synergy of c-Myb through a repressor-activator switch leading to differential p300 recruitment. 2038 74

p73, a recently described member of the p53 family of transcription factors, undergoes a number of posttranslational modifications, inducing cell cycle arrest and apoptosis. In the present study, we demonstrate that PIASy, a member of the PIAS SUMO-ligase family, interacts with p73alpha, and that PIASy-mediated sumoylation promotes proteasomal degradation of p73alpha. PIASy overexpression inhibits p73alpha-mediated transcription of p21, with a reduction of cells in G1 and cell cycle reentry. These results suggest that PIASy plays an important role in regulation of p73alpha transcriptional activity and is also a regulator of the cell cycle machinery.
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PMID:PIASy interacts with p73alpha and regulates cell cycle in HEK293 cells. 2047 36

Many functional subdomains, including promyelocytic leukemia nuclear bodies (PML NBs), are formed in the mammalian nucleus. Various proteins are constitutively or transiently accumulated in PML NBs in a PML-dependent manner. MORC3 (microrchidia family CW-type zinc-finger 3), also known as NXP2, which consists of GHL-ATPase, a CW-type zinc-finger and coiled-coil domains, is localized in PML NBs, where it recruits and activates p53 to induce cellular senescence. Interestingly, we found that MORC3 can form PML-independent nuclear domains (NDs) in mouse hematopoietic cells and even in Pml-deficient cells. Here, we show that MORC3 colocalizes with PML by a two-step molecular mechanism: the PML-independent formation of MORC3 NDs by the ATPase cycle, and the association of MORC3 with PML via the SUMO1-SUMO-interacting motif (SIM). Similarly to other members of the GHL-ATPase family, MORC3 functions as a 'molecular clamp'. ATP binding induces conformational changes in MORC3, leading to the formation of MORC3 NDs, and subsequent ATP hydrolysis mediates the diffusion and binding of MORC3 to the nuclear matrix. MORC3 might clamp DNA or nucleosomes in MORC3 NDs via the CW domain. Furthermore, the SUMOylation of MORC3 at five sites was involved in the association of MORC3 with PML, and SUMO1-unmodified MORC3 formed NDs independently of PML.
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PMID:Two-step colocalization of MORC3 with PML nuclear bodies. 2050 96


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