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)

B9L/BCL9-2, a novel beta-catenin-interacting protein, plays an important role in colorectal carcinogenesis by translocating beta-catenin to the nucleus and enhancing beta-catenin-T-cell factor-mediated transcription. To elucidate the role of B9L in breast cancers, we studied B9L expression in ductal carcinoma in situ (DCIS) and invasive ductal carcinoma (IDC) of the breast immunohistochemically and compared it to the immunohistochemical expression of known proteins involved in breast carcinogenesis. In breast tissues, B9L immunoreactivity was present exclusively in the nuclei of normal and neoplastic ductal cells. In DCIS, immunohistochemical B9L expression was significantly associated with the tumor nuclear grade, comedo necrosis and the expression of ErbB2/HER-2, c-myc and p53. In IDC, B9L expression was correlated with ErbB2/HER-2 expression and tumor nuclear grade only. In both DCIS and IDC, immunohistochemical B9L expression was not related to the expression of cytoplasmic beta-catenin. We demonstrated that nuclear B9L expression was closely associated with the high nuclear grade cancer phenotype and the expression of ErbB2/HER-2 in breast cancers.
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PMID:Immunohistochemical expression of the beta-catenin-interacting protein B9L is associated with histological high nuclear grade and immunohistochemical ErbB2/HER-2 expression in breast cancers. 1730

As a major negative regulator of p53, the MDM2 oncogene plays an important role in carcinogenesis and tumor progression. MDM2 promotes p53 proteasomal degradation and negatively regulates p53 function. The mechanisms by which the MDM2-p53 interaction is regulated are not fully understood, although several MDM2-interacting molecules have recently been identified. To search for novel MDM2-binding partners, we screened a human prostate cDNA library by the yeast two-hybrid assay using full-length MDM2 protein as the bait. Among the candidate proteins, ribosomal protein S7 was identified and confirmed as a novel MDM2-interacting protein. Herein, we demonstrate that S7 binds to MDM2, in vitro and in vivo, and that the interaction between MDM2 and S7 leads to modulation of MDM2-p53 binding by forming a ternary complex among MDM2, p53 and S7. This results in the stabilization of p53 protein through abrogation of MDM2-mediated p53 ubiquitination. Consequently, S7 overexpression increases p53 transactivational activities, induces apoptosis, and inhibits cell proliferation. The identification of S7 as a novel MDM2-interacting partner contributes to elucidation of the complex regulation of the MDM2-p53 interaction and has implications in cancer prevention and therapy.
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PMID:Ribosomal protein S7 as a novel modulator of p53-MDM2 interaction: binding to MDM2, stabilization of p53 protein, and activation of p53 function. 1731 Sep 83

We have previously identified mouse DDA3 as a p53-inducible gene. To explore the functional role of DDA3, we screened a mouse brain cDNA library by the yeast two-hybrid assay, and identified the microtubule plus-end binding protein EB3 as a DDA3-interacting protein. Binding of DDA3 to EB3 was verified by glutathione S-transferase (GST) pull-down assay and subcellular colocalization; co-immunoprecipitation further indicated that interaction of these two proteins within cells required intact microtubules. Domains of DDA3-EB3 interaction were mapped by GST pull-down assay to amino acids 118-241 and 242-329 of DDA3 and the N- and C-termini of EB3. Immunofluorescence analysis revealed colocalization of DDA3 with microtubules in various cell phases, and regions encompassing aa 118-241 and 242-329 contained microtubule-interacting and bundling activities. In vitro microtubule-binding assay showed that DDA3 and EB3 associated directly with microtubules, and cooperated with each other for microtubule binding. In addition, DDA3 bound to the EB3 interacting partner adenomatous polyposis coli 2 (APC2), a homolog of the tumor suppressor APC, which is a component of the beta-catenin destruction complex. Ectopic expression of DDA3 and EB3 enhanced beta-catenin-dependent transactivation and cyclin D1 production, whereas knockdown of endogenous DDA3 or EB3 inhibited beta-catenin-mediated transactivation and the ability of cells to form colonies. Together, our results identify DDA3 as a novel microtubule-associated protein that binds to EB3, and implicate DDA3 and EB3 in the beta-catenin-mediated growth signaling.
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PMID:p53 downstream target DDA3 is a novel microtubule-associated protein that interacts with end-binding protein EB3 and activates beta-catenin pathway. 1731 Sep 96

As a multifunctional protein, Yin Yang 1 (YY1) has been demonstrated to regulate both gene expression and protein posttranslational modifications. However, gaps still exist in our knowledge of how YY1 can be modified and what the consequences of its modifications are. Here we report that YY1 protein can be sumoylated both in vivo and in vitro. We have identified lysine 288 as the major sumoylation site of YY1. We also discovered that PIASy, a SUMO E3 ligase, is a novel YY1-interacting protein and can stimulate the sumoylation of YY1 both in vitro and in vivo. Importantly, the effects of PIASy mutants on in vivo YY1 sumoylation correlate with the YY1-PIASy interaction but do not depend on the RING finger domain of PIASy. This regulation is unique to YY1 sumoylation because PIASy-mediated p53 sumoylation still relies on the integrity of PIASy, which is also true of all of the previously identified substrates of PIASy. In addition, PIASy colocalizes with YY1 in the nucleus, stabilizes YY1 in vivo, and differentially regulates YY1 transcriptional activity on different target promoters. This study demonstrates that YY1 is a target of SUMOs and reveals a novel feature of a SUMO E3 ligase in the PIAS family that selectively stimulates protein sumoylation independent of the RING finger domain.
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PMID:PIASy-mediated sumoylation of Yin Yang 1 depends on their interaction but not the RING finger. 1735 73

S100A4 (also known as Mts1, metastasin, p9Ka, pEL98, CAPL, calvasculin, Fsp-1, placental calcium-binding protein) belongs to the family of EF-hand calcium-binding proteins, whose expression is elevated in a number of pathological conditions. Although it is well documented that S100A4 is expressed in cancer cells and contributes to tumor cell motility and metastatic progression, the exact underlying mechanisms remain elusive. An important characteristic feature of S100 proteins is their dual function, inside and outside the cell. In this review, we focus on the intracellular function of S100A4. The review contains structural analysis of S1004 in comparison with other members of S100 proteins. Possible modes of the interaction of S100 proteins with targets are described. Several examples of best-studied molecular interactions involving S100A4 with heavy chain of nonmuscle myosin IIA, LAR-interacting protein liprin beta1 and tumor suppressor protein p53 are provided. We suggest that the binding of S100A4 to these molecules is critical for the S100A4 function. Further studies of the implications of these interactions in different molecular pathways may shed additional light on the role of S100A4 protein in the control of tumor cell motility and migration. We discuss the approaches for down-regulation of S100A4 expression and their potential for application in the clinics.
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PMID:Metastasis-associated protein S100A4: spotlight on its role in cell migration. 1750 19

The tumor suppressor, p53, plays critical roles in the cell cycle progression, DNA repair and apoptosis. The PIAS proteins (protein inhibitor of activated STAT) were originally identified as inhibitors of the JAK-STAT pathway. Subsequently, crosstalk between the PIAS proteins and other signaling pathways has been shown to be involved in various cellular processes. Particularly, previous studies have demonstrated that PIAS proteins regulate p53-mediated transcription through sumoylation. hZimp10, also named zmiz1, is a novel PIAS-like protein and functions as a transcriptional co-activator. We recently identified p53 to be an hZimp10 interacting protein in the yeast two-hybrid screen. The interaction between p53 and hZimp10 was confirmed by GST pull-down and co-immunoprecipitation assays. Co-localization of p53 and hZimp10 proteins was also observed within cell nuclei by immunostaining. Moreover, we show that expression of exogenous hZimp10 enhances the transcriptional activity of p53 and knockdown of endogenous hZimp10 reduces the transcriptional activity of p53. Furthermore, using chromatin immunoprecipitation assays, we demonstrate that hZimp10 binds to p53 on the p21 promoter. Finally, p53-mediated transcription is significantly impaired in Zimp10 null embryonic fibroblasts. Taken together, these results provide the first line of evidence to demonstrate a role for Zimp10 in regulating p53 function.
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PMID:The novel PIAS-like protein hZimp10 is a transcriptional co-activator of the p53 tumor suppressor. 1758 85

Sirt1 is an NAD+-dependent deacetylase that plays a role in cellular processes such as transcriptional regulation, stress response, longevity and apoptosis. Sirt1 deacetylates histone proteins and certain transcription factors such as p53, CTIP2 (chicken ovalbumin upstream promoter-transcription factor-interacting protein 2), FOXO (forkhead box O) and NF-kappaB (nuclear factor kappaB). To identify potential Sirt1-interacting factors, we performed a yeast two-hybrid screen. The screen identified TLE1 (transducin-like enhancer of split-1) as a possible Sirt1-interacting factor, which was then confirmed by co-immunoprecipitation. TLE1 is a non-DNA binding co-repressor for several transcriptional factors including NF-kappaB. We have demonstrated using co-transfection assays that Sirt1 and TLE1 repress NF-kappaB activity. The catalytic mutant of Sirt1, Sirt1-H363Y, and the N-terminal Sirt1 fragment (amino acids 1-270) also show similar repression activity, suggesting that the deacetylase activity of Sirt1 may not be critical for its effect on NF-kappaB activity. Furthermore, analysis in Sirt1-null MEFs (murine embryonic fibroblasts) and HeLa cells stably expressing siRNA (small interfering RNA) specific to Sirt1 or TLE1 demonstrate that both Sirt1 and TLE1 are required for negative regulation of NF-kappaB activity. Taken together, these results suggest that the interaction between Sirt1 and TLE1 is important for mediating repression of NF-kappaB activity.
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PMID:Sirt1 interacts with transducin-like enhancer of split-1 to inhibit nuclear factor kappaB-mediated transcription. 1768 Jul 80

Ubiquitylation appears to be involved in the membrane trafficking system including endocytosis, exocytosis, and ER-to-Golgi transport. We found that PIRH2, which was identified as an interacting protein for androgen receptor or p53, interacts with and ubiquitylates the epsilon-subunit of coatmer complex, epsilon-COP. PIRH2 promotes the ubiquitylation of epsilon-COP in vitro and in vivo and consequently promotes the degradation of epsilon-COP. The interaction between PIRH2 and epsilon-COP is affected by the presence of androgen, and PIRH2 in the presence of androgen promotes ubiquitylation of epsilon-COP in vivo. Furthermore, overexpression of the wild type of PIRH2 in prostate cancer cells causes downregulation of the secretion of prostate-specific antigen (PSA), a secretory protein in prostate epithelial cells and one of diagnostic markers for prostate cancer. Our results indicate that PIRH2 functions as a regulator for COP I complex.
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PMID:Ubiquitylation of epsilon-COP by PIRH2 and regulation of the secretion of PSA. 1772 9

TIP30 (Tat-interacting protein 30), a newly found proapoptotic factor, appears to be involved in multiple functions including metabolic suppression, apoptosis induction, and diminishing angiogenic properties. In the present study, we reported that mitochondrial events were required for apoptosis induced by TIP30 in hepatocellular carcinoma cells (HCC cells). Translocation of Bax was essential for TIP30-induced apoptosis, whereas overexpression of the anti-apoptotic protein Bcl-xL delayed both second mitochondria-derived activator of caspases (Smac/DIABLO) release and onset of apoptosis. Furthermore, TIP30-induced apoptosis was dependent on caspase activity because the pan-caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp (OMe)-fluoromethyl ketone (z-VAD-fmk) blocked DNA fragmentation. Release of Smac/DIABLO from the mitochondria through the TIP30-P53-Bax cascade was required to remove the inhibitory effect of XIAP (X-linked Inhibitor of Apoptosis) and allowed apoptosis to proceed. Our results showed for the first time that Bax-dependent release of Smac/DIABLO, cytochrome c and AIF from the mitochondria mediated the contribution of the mitochondrial pathway to TIP30-mediated apoptosis. Our data suggested that adenovirus-mediated overexpression of TIP30 was capable of inducing therapeutic programmed cell death in vitro by activating the mitochondrial pathway of apoptosis. On the basis of these studies, elucidating the mechanism by which TIP30 induces cell death might establish it as an anticancer approach.
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PMID:Tip30-induced apoptosis requires translocation of Bax and involves mitochondrial release of cytochrome c and Smac/DIABLO in hepatocellular carcinoma cells. 1799 90

Vascular permeability factor/vascular endothelial growth factor (VPF/VEGF), one of the crucial pro-angiogenic factors, functions as a potent inhibitor of endothelial cell (EC) apoptosis. Previous progress has been made towards delineating the VPF/VEGF survival signaling downstream of the activation of VEGFR-2. Here, we seek to define the function of NRP-1 in VPF/VEGF-induced survival signaling in EC and to elucidate the concomitant molecular signaling events that are pivotal for our understanding of the signaling of VPF/VEGF. Utilizing two different in vitro cell culture systems and an in vivo zebrafish model, we demonstrate that NRP-1 mediates VPF/VEGF-induced EC survival independent of VEGFR-2. Furthermore, we show here a novel mechanism for NRP-1-specific control of the anti-apoptotic pathway in EC through involvement of the NRP-1-interacting protein (NIP/GIPC) in the activation of PI-3K/Akt and subsequent inactivation of p53 pathways and FoxOs, as well as activation of p21. This study, by elucidating the mechanisms that govern VPF/VEGF-induced EC survival signaling via NRP-1, contributes to a better understanding of molecular mechanisms of cardiovascular development and disease and widens the possibilities for better therapeutic targets.
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PMID:Neuropilin-1 modulates p53/caspases axis to promote endothelial cell survival. 1800 May 34


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