Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P43146 (tumour suppressor)
 5,935 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The E1B-55K product from human adenovirus is a substrate of the small ubiquitin-related modifier (SUMO)-conjugation system. SUMOylation of E1B-55K is required to transform primary mammalian cells in cooperation with adenovirus E1A and to repress p53 tumour suppressor functions. The biochemical consequences of SUMO1 conjugation of 55K have so far remained elusive. Here, we report that E1B-55K physically interacts with different isoforms of the tumour suppressor protein promyelocytic leukaemia (PML). We show that E1B-55K binds to PML isoforms IV and V in a SUMO1-dependent and -independent manner. Interaction with PML-IV promotes the localization of 55K to PML-containing subnuclear structures (PML-NBs). In virus-infected cells, this process is negatively regulated by other viral proteins, indicating that binding to PML is controlled through reversible SUMOylation in a timely coordinated manner. These results together with earlier work are consistent with the idea that SUMOylation regulates targeting of E1B-55K to PML-NBs, known to control transcriptional regulation, tumour suppression, DNA repair and apoptosis. Furthermore, they suggest that SUMO1-dependent modulation of p53-dependent growth suppression through E1B-55K PML-IV interaction has a key role in adenovirus-mediated cell transformation.
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PMID:SUMO modification of E1B-55K oncoprotein regulates isoform-specific binding to the tumour suppressor protein PML. 2063 99

The nuclear lamina provides structural support to the nucleus and has a central role in nuclear organization and gene regulation. Defects in its constituents, the lamins, lead to a class of genetic diseases collectively referred to as laminopathies. Using live cell imaging, we observed the occurrence of intermittent, non-lethal ruptures of the nuclear envelope in dermal fibroblast cultures of patients with different mutations of lamin A/C. These ruptures, which were absent in normal fibroblasts, could be mimicked by selective knockdown as well as knockout of LMNA and were accompanied by the loss of cellular compartmentalization. This was demonstrated by the influx of cytoplasmic transcription factor RelA and regulatory protein Cyclin B1 into the nucleus, and efflux of nuclear transcription factor OCT1 and nuclear structures containing the promyelocytic leukemia (PML) tumour suppressor protein to the cytoplasm. While recovery of enhanced yellow fluorescent protein-tagged nuclear localization signal in the nucleus demonstrated restoration of nuclear membrane integrity, part of the mobile PML structures became permanently translocated to the cytoplasm. These satellite PML structures were devoid of the typical PML body components, such as DAXX, SP100 or SUMO1. Our data suggest that nuclear rupture and loss of compartmentalization may add to cellular dysfunction and disease development in various laminopathies.
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PMID:Repetitive disruptions of the nuclear envelope invoke temporary loss of cellular compartmentalization in laminopathies. 2183 85

The membrane association of the tumour suppressor phosphatase and tensin homologue (PTEN) is required to oppose the phosphatidylinositol-3-kinase/AKT pathway by dephosphorylation of phosphatidylinositol-3,4,5-triphosphate (PIP3). How cytosolic PTEN interacts with its main substrate, PIP3, localized at the inner face of plasma membrane remains unclear. Here we show that PTEN is covalently modified by SUMO1 at both K(266) and K(254) sites in the C2 domain of PTEN. SUMO1 modification at K(266) located in the CBR3 loop, which has a central role in PTEN membrane association, mainly facilitates cooperative binding of PTEN to the plasma membrane by electrostatic interactions. This results in the downregulation of the phosphatidylinositol-3 kinase/AKT pathway and consequently, suppression of anchorage-independent cell proliferation and tumour growth in vivo. Our data demonstrate a molecular mechanism whereby SUMO1 modification is required for PTEN tumour suppressor function by controlling PTEN membrane association and regulation of the phosphatidylinositol-3 kinase/AKT pathway.
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PMID:SUMO1 modification of PTEN regulates tumorigenesis by controlling its association with the plasma membrane. 2271 53