Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The tumor suppressor p53 is a key transcriptional factor regulating the induction of cellular senescence by oncogenic signals. The activity of p53 is regulated by recruitment into promyelocytic leukemia (PML)-nuclear bodies (NBs) as well as by stabilization through posttranslational modifications such as phosphorylation and acetylation. Here we found that MORC3 (microrchidia3)-ATPase activated p53 and induced cellular senescence in normal human and mouse fibroblasts but not p53-/- fibroblasts. Conversely, genotoxic stress-induced phosphorylation and stabilization of p53 but barely increased its transcriptional activity in Morc3-/- fibroblasts. MORC3 localized on PML-NBs in presence of PML and mediated recruitment of p53 and CREB-binding protein (CBP) into PML-NBs. In contrast, expression of ATPase activity-deficient mutant MORC3-E35A or siRNA repression of MORC3 impaired the localization of p53 and Sp100 but not CBP on PML-NBs. These results suggest that MORC3 regulates p53 activity and localization into PML-NBs. We identified a new molecular mechanism that regulates the activity of nuclear proteins by localization to a nuclear subdomain.
 ...
PMID:Dynamic regulation of p53 subnuclear localization and senescence by MORC3. 1733 4

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.
 ...
PMID:Two-step colocalization of MORC3 with PML nuclear bodies. 2050 96

Glioblastoma multiforme (GBM) displays high resistance to radiation and chemotherapy, due to the presence of a fraction of GBM stem-like cells (GSLCs), which are thus representing the target for GBM elimination. Since mesenchymal stem cells (MSCs) display high tumor tropism, we examined possible antitumor effects of the secreted factors from human MSCs on four GSLC lines (NCH421k, NCH644, NIB26, and NIB50). We found that conditioned media from bone marrow and umbilical cord-derived MSCs (MSC-CM) mediated cell cycle arrest of GSLCs by downregulating cyclin D1. PCR arrays revealed significantly deregulated expression of 13 genes associated with senescence in NCH421k cells exposed to MSC-CM. Among these, ATM, CD44, COL1A1, MORC3, NOX4, CDKN1A, IGFBP5, and SERPINE1 genes were upregulated, whereas IGFBP3, CDKN2A, CITED2, FN1, and PRKCD genes were found to be downregulated. Pathway analyses in GO and KEGG revealed their association with p53 signaling, which can trigger senescence via cell cycle inhibitors p21 or p16. For both, upregulated expression was proven in all four GSLC lines exhibiting senescence after MSC-CM exposure. Moreover, MSC paracrine signals were shown to increase the sensitivity of NCH421k and NCH644 cells toward temozolomide, possibly by altering them toward more differentiated cell types, as evidenced by vimentin and GFAP upregulation, and Sox-2 and Notch-1 downregulation. Our findings support the notion that MSCs posses an intrinsic ability to inhibit cell cycle and induce senescence and differentiation of GSLCs.
...
PMID:Paracrine effects of mesenchymal stem cells induce senescence and differentiation of glioblastoma stem-like cells. 2580 80

The NS1protein, a nonstructural protein of Tembusu virus, plays a key role in the pathogenesis of TMUV. To research host proteins that interact with NS1 protein, the cDNA library of duck embryo fibroblasts (DEF) was successfully constructed. The recombinant plasmid, pGBKT7-NS1, was transformed into the yeast Y2H to be cloned and tested for autoactivation and toxicity. The autoactivation and toxicity test of bait showed that the yeast two hybrid test could be carried out normally. A total of 7 clones from the library were got by Yeast Two-Hybrid System, and 4 proteins, including RPS7, MORC3, GABARAPL1 and MTSS1, may be interacted with DTMUV NS1 after sequencing and blast. Then we chose the host protein of RPS7 for GST pull down assay and the recombinant plasmid of pGEX-6p-1-NS1and pEGFP-RPS7 were constructed. Then the proteins of GST-NS1 and GFP-RPS7 were successfully expressed in vitro for GST pull down assay. The results showed that there was a real interaction between the two proteins when the protein of GST-NS1-GFP-RPS7 was obtained eventually. The Real-time RT-PCR was used to detect the expression level of RPS7, MDM2 and P53 mRNA after the recombinant plasmid of pEGFP-NS1 was expressed in 293 T cells. It is showed that the expression of NS1 protein causes the low expression of RPS7 and MDM2 mRNA and eventually causes the high expression of P53 mRNA. This research lays the foundation for clarifying the pathogenic mechanism of Tembusu virus and the function of NS1 protein in virus propagation process.
 ...
PMID:Screening of the proteins interacting with NS1 of TMUV by yeast two-hybrid system and the identification of the function of the interacted protein. 2988 72