MBP1: a novel mutant p53-specific protein partner with oncogenic properties

Gallagher, William M.; Argentini, Manuela; Sierra, Véronique; Bracco, Laurent; Debussche, Laurent; Conseiller, Emmanuel

doi:10.1038/sj.onc.1202937

Cited by 54 publications

(58 citation statements)

References 35 publications

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“…In addition, PIAS1 was identified as an E3 ligase for sumoylation of p53, which requires the RING-finger domain (residues 325-382) of PIAS1 (20). However, the functional role of PIAS1 in the activity of p53 has not been investigated in these studies (20,29). In our study, PIAS1-(400 -651) lacking the RING-finger efficiently activated p53-mediated gene expression (Fig.…”

Section: Pias1 Induces P53-dependent Expression Of Cyclin-dependent Kmentioning

confidence: 59%

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Activation of p53 by Protein Inhibitor of Activated Stat1 (PIAS1)

Megidish¹,

Xu²,

Xu³

2002

Journal of Biological Chemistry

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The tumor suppressor protein p53 functions as a transcriptional factor that activates genes controlling cell cycle arrest and apoptosis. Here, we report that protein inhibitor of activated Stat1 (PIAS1) interacts with the tetramerization and C-terminal regulatory domains of p53 in yeast two-hybrid analyses. Endogenous PIAS1 is also associated with endogenous p53 in mammalian cells. Ectopic expression of PIAS1 activates p53-mediated expression in mouse embryonic fibroblast cells (p53 ؊/؊ ) as well as a variety of other cell lines. Furthermore, ectopic expression of PIAS1 induces p53-mediated expression of cyclin-dependent kinase inhibitor p21 and G 1 arrest of the cell cycle in H1299 cells. In addition, a PIAS1 mutant without the RING-finger domain required for sumoylation could still activate p53-mediated gene expression, indicating that activation of p53 by PIAS1 does not require the RING-finger domain. Taken together, our results suggest that PIAS1 is a novel activator of p53.The tumor suppressor protein p53 is normally very short-lived and remains at very low levels through proteasomal degradation in unstressed mammalian cells. In response to damaged DNA, nucleotide depletion, hypoxia, oncogenes, and other genotoxic stresses, p53 accumulates dramatically in nucleus and functions as a transcriptional activator (1-4). Activation of p53 leads to cell cycle arrest or apoptosis by inducing a number of genes including cyclin-dependent kinase inhibitor p21 and apoptotic genes such as Bax. Although the exact mechanisms by which some of these stress signals are transduced to p53 are not known, signaling to p53 is thought to be mediated by upstream p53 regulators in at least three distinguishable pathways (5). The first pathway transduces signals of DNA damage induced by ionizing radiation, which activates ATM, Chk2, and subsequently p53. The second pathway is mediated by p14 ARF -MDM2 interaction (6), which is triggered by oncogenic signals such as Ras and Myc. The third pathway is turned on by a wide array of chemotherapeutic drugs, UV light, and protein kinase inhibitors, which requires kinases ATR and casein kinase II. There are additional proteins that can activate p53, but the significance of some of these interactions remains to be elucidated (1).The key negative regulator of the p53 network is MDM2. Transcription of MDM2 is itself activated by p53. However, MDM2 protein can both inhibit the transcriptional activity of p53 and target p53 for ubiquitin-mediated protein degradation (7-9), forming a negative regulatory loop for p53 function. Interference of the p53 and MDM2 interaction appears to be a main convergent point for many of the stress signals, resulting in stabilization and activation of p53 (10).The discovery of p63 and p73, the p53 family members, added a new level of complexity to understanding the p53 network (11). Both p63 and p73 produce multiple transcripts, which could either activate or inhibit p53-mediated gene expression. In contrast to p53, p63 and p73 do not interact with most viral proteins...

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Section: Pias1 Induces P53-dependent Expression Of Cyclin-dependent Kmentioning

confidence: 59%

“…During this project, PIAS1 was independently identified as an interactor of mutant p53 in a two-hybrid screening (29). In addition, PIAS1 was identified as an E3 ligase for sumoylation of p53, which requires the RING-finger domain (residues 325-382) of PIAS1 (20).…”

Section: Pias1 Induces P53-dependent Expression Of Cyclin-dependent Kmentioning

confidence: 99%

Activation of p53 by Protein Inhibitor of Activated Stat1 (PIAS1)

Megidish¹,

Xu²,

Xu³

2002

Journal of Biological Chemistry

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“…With respect to the latter, signal sequence polymorphisms in the Fibulin-4 gene prevent its secretion from human colon cancer cells (28). This intracellular variant of Fibulin-4 then interacts with and inhibits the activity of p53, leading to enhanced proliferation of tumor cells (22). Thus, expression of Fibulins 3 and 4, like that of FBLN-5, governs proliferation in a cell type-specific manner.…”

Section: Discussionmentioning

confidence: 99%

Context-specific Effects of Fibulin-5 (DANCE/EVEC) on Cell Proliferation, Motility, and Invasion

Schiemann¹,

Blobe²,

Kalume³

et al. 2002

Journal of Biological Chemistry

144

100

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The Fibulin gene family comprises five distinct genes that encode more than eight protein products via alternative splicing. Fibulins are widely expressed secretory proteins found in the blood and in the basement membranes and stroma of most tissues, where they self-associate (e.g. Fibulins 1 and 2) (1, 2) and/or interact with a variety of extracellular matrix components, including fibronectin, laminin, nidogen, aggrecan, versican, endostatin, and elastin (3-5). Thus, Fibulins likely participate in the assembly and stabilization of extracellular matrix structures; they also have been implicated in regulating organogenesis, vasculogenesis, fibrogenesis, and tumorigenesis (6 -8). Although the molecular mechanisms underlying the various biological activities of Fibulins remain to be elucidated, recent work suggests that Fibulins may interact directly with cell surface receptors, raising the possibility that these secretory proteins also function in mediating cell-cell and cell-matrix communication.The newest member of the Fibulin family is Fibulin-5 (FBLN-5; also known as EVEC (9) or DANCE (10)), 1 a 448-amino acid glycoprotein with interesting structural features; it contains an integrin-binding RGD motif, six calcium-binding epidermal growth factor-like repeats, a Pro-rich insert in the first calcium-binding epidermal growth factor-like repeat, and a globular C-terminal domain (9, 10). Functionally, FBLN-5 binds ␣ v ␤ 3 , ␣ v ␤ 5 , and ␣ 9 ␤ 1 integrins (4) and mediates endothelial cell adhesion via its RGD motif (10). In response to mechanical injury, FBLN-5 expression is induced dramatically in vascular endothelial and smooth muscle cells (9, 10), suggesting that FBLN-5 regulates vasculogenesis and endothelial cell function. Inactivation of the FBLN-5 gene in mice produces profound elastinopathy in the skin, lung, and vasculature (4, 5), demonstrating its importance in scaffolding cells to elastic fibers.Despite these recent advances, many questions regarding the role of FBLN-5 in mammalian biology remain to be answered, particularly (i) what are the signaling systems/molecules that regulate (ii) what are the effects of FBLN-5 on cell proliferation, migration, and invasion, and (iii) what are the signaling systems/molecules stimulated by FBLN-5. Through the use of expression proteomics, we show here that FBLN-5 is a novel TGF-␤-inducible protein that

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“…Furthermore, several PIAS proteins were shown to act as either positive or negative coregulators of nuclear hormone receptors (15, 16). PIAS1, PIASx␣, and PIASy had also been isolated as p53-interacting proteins in two-hybrid screens by using p53 as bait (17)(18)(19), but the functional significance of this interaction has remained unclear. Intriguingly, one of these screens identified both Ubc9 and PIAS1.…”

mentioning

confidence: 99%

Members of the PIAS family act as SUMO ligases for c-Jun and p53 and repress p53 activity

Schmidt

Müller

2002

Proc. Natl. Acad. Sci. U.S.A.

415

331

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The activity of the p53 tumor suppressor protein and the c-Jun protooncogene is regulated by posttranslational modifications, such as phosphorylation or ubiquitination. In addition, covalent attachment of the ubiquitin-like modifier SUMO appears to modulate their transcriptional activity. Sumoylation proceeds via an enzymatic pathway that is mechanistically analogous to ubiquitination, but requires a different E1-activating enzyme and Ubc9, a SUMO-specific E2-conjugating enzyme. Here, we show that two members of the PIAS family, PIAS1 and PIASx␤, act as specific E3-like ligases that promote sumoylation of p53 and c-Jun in vitro and in vivo. The PIAS proteins physically interact with both p53 and c-Jun. In addition, they bind to Ubc9, suggesting that they recruit the E2 enzyme to their respective substrate. The SUMO ligase activity requires the conserved zinc-finger domain, which is distantly related to the essential RING-finger motif, found in a subset of ubiquitin ligases. Furthermore, similar to RING-type ubiquitin ligases, PIASx␤ can catalyze its own modification. Hence, these data further extend the analogy between the ubiquitin and SUMO pathway. Strikingly, PIAS proteins strongly repress the transcriptional activity of p53, suggesting that the PIAS-SUMO pathway plays a crucial role in the regulation of p53 and presumably other transcription factors. Many cellular key functions are regulated by the covalent modification of proteins with the ubiquitin-like SUMO-1 modifier (1-3). Two important examples are the transcriptional activity of the c-Jun protooncogene and the p53 tumor suppressor, which seem to be regulated by sumoylation (4-6). Mammalian SUMO-1 and its close relatives, SUMO-2 and SUMO-3, are about 18% identical to ubiquitin and are conjugated via an enzymatic cascade that requires a SUMO-specific, heterodimeric E1-activating enzyme (Aos1͞Uba2) and a single E2-type conjugating enzyme, Ubc9. In the ubiquitin pathway, at least one additional factor, called E3 or ubiquitin ligase, is required for substrate recognition and formation of an isopeptide bond between ubiquitin and the target protein. Because the SUMO-specific E2 enzyme Ubc9 has been shown to physically interact with almost all known SUMO substrates in yeast twohybrid assays, Ubc9 was considered to be sufficient for substrate recognition.Very recently, however, in the yeast Saccharomyces cerevisiae, the Siz1 and Siz2 proteins were identified as E3-like factors that promote SUMO conjugation to yeast proteins, in particular to proteins of the septin family (7-9). Siz proteins are homologous to members of the mammalian PIAS (protein inhibitor of activated Stat) family of proteins. In humans, this family consists of at least five members: PIAS1, PIAS3, the ␣ and ␤ splice variants of PIASx, and PIASy (10). PIAS proteins were initially identified as specific inhibitors of Stat transcription factors. PIAS1 and PIAS3 block the DNA binding activity of activated Stat1 and Stat3, respectively, and inhibit Stat-mediated transcription (11, 12). Subsequentl...

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MBP1: a novel mutant p53-specific protein partner with oncogenic properties

Cited by 54 publications

References 35 publications

Activation of p53 by Protein Inhibitor of Activated Stat1 (PIAS1)

Activation of p53 by Protein Inhibitor of Activated Stat1 (PIAS1)

Context-specific Effects of Fibulin-5 (DANCE/EVEC) on Cell Proliferation, Motility, and Invasion

Members of the PIAS family act as SUMO ligases for c-Jun and p53 and repress p53 activity

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