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Query: UNIPROT:P06889 (Mol)
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Silenced expression of the FMR1 gene is responsible for the fragile X syndrome. The FMR1 gene codes for an RNA binding protein (FMRP), which can shuttle between the nucleus and the cytoplasm and is found associated to polysomes in the cytoplasm. By two-hybrid assay in yeast, we identified a novel protein interacting with FMRP: nuclear FMRP interacting protein (NUFIP). NUFIP mRNA expression is strikingly similar to that of the FMR1 gene in neurones of cortex, hippocampus and cerebellum. At the subcellular level, NUFIP colocalizes with nuclear isoforms of FMRP in a dot-like pattern. NUFIP presents a C2H2 zinc finger motif and a nuclear localization signal, but has no homology to known proteins and shows RNA binding activity in vitro. NUFIP does not interact with the FMRP homologues encoded by the FXR1 and FXR2 genes. Thus, these results indicate a specific nuclear role for FMRP.
Hum Mol Genet 1999 Dec
PMID:A novel RNA-binding nuclear protein that interacts with the fragile X mental retardation (FMR1) protein. 1055 5

We previously identified a novel TATA-binding protein (TBP)-interacting protein (TIP120) from the rat liver. Here, in an RNA polymerase II (RNAP II)-reconstituted transcription system, we demonstrate that recombinant TIP120 activates the basal level of transcription from various kinds of promoters regardless of the template DNA topology and the presence of TFIIE/TFIIH and TBP-associated factors. Deletion analysis demonstrated that a 412-residue N-terminal domain, which includes an acidic region and the TBP-binding domain, is required for TIP120 function. Kinetic studies suggest that TIP120 functions during preinitiation complex (PIC) formation at the step of RNAP II/TFIIF recruitment to the promoter but not after the completion of PIC formation. Electrophoretic mobility shift assays showed that TIP120 enhanced PIC formation, and TIP120 also stimulated the nonspecific transcription and DNA-binding activity of RNAP II. These lines of evidence suggest that TIP120 is able to activate basal transcription by overcoming a kinetic impediment to RNAP II/TFIIF integration into the TBP (TFIID)-TFIIB-DNA-complex. Interestingly, TIP120 also stimulates RNAP I- and III-driven transcription and binds to RPB5, one of the common subunits of the eukaryotic RNA polymerases, in vitro. Furthermore, in mouse cells, ectopically expressed TIP120 enhances transcription from all three classes (I, II, and III) of promoters. We propose that TIP120 globally regulates transcription through interaction with basal transcription mechanisms common to all three transcription systems.
Mol Cell Biol 1999 Dec
PMID:TATA-Binding protein-interacting protein 120, TIP120, stimulates three classes of eukaryotic transcription via a unique mechanism. 1056 21

The cucumber mosaic virus (CMV)-encoded 2b protein has been implicated to play a role in long distance movement of the virus through the plant's transport system. It is unknown, however, how it mediates virus movement and whether any intrinsic components of plant cells also participate in this process. To isolate a host factor that interacts with 2b, the yeast two-hybrid system was used. First, it was found that the 2b protein per se could function as a transcriptional activator in yeast. However, its two carboxyl terminal deletion mutants, 2bdelta98 and 2bdelta95, which lacked 12 and 15 amino acids from the carboxyl terminus respectively, showed complete absence of transcriptional activation in yeast. A tobacco cDNA library expressing the GAL4 activation domain fusion proteins was screened using 2bdelta98 as a bait. A clone named 2bip (2b-interacting protein) was isolated whose translation product apparently interacted with 2b. Consistent with this observation, bacterially expressed GST-2bip fusion protein bound tightly to 2bdelta95 and 2bdelta98 polypeptides in vitro, as well as to the unmodified 2b protein. Nucleotide sequencing and database searches revealed that the amino acid sequence deduced from it was similar to a prokaryotic LytB protein and an unknown protein of Arabidopsis. DNA and RNA gel blot analyses showed that 2bip-related sequences were present in the tobacco genome and that transcripts corresponding to 2bip were expressed constitutively in various plant organs and in response to CMV infection. These results suggest 2bip as a novel host factor that is capable of interacting with CMV2b.
Mol Cells 1999 Oct 31
PMID:Isolation of a putative tobacco host factor interacting with cucumber mosaic virus-encoded 2b protein by yeast two-hybrid screening. 1059 45

An androgen receptor (AR) interacting protein was isolated from a HeLa cell cDNA library by two-hybrid screening in yeast using the AR DNA+ligand binding domains as bait. The protein has sequence identity with human protein inhibitor of activated signal transducer and activator of transcription (PIAS1) and human Gu RNA helicase II binding protein (GBP). Binding of PIAS1 to human AR DNA+ligand binding domains was androgen dependent in the yeast liquid beta-galactosidase assay. Activation of binding by dihydrotestosterone was greater than testosterone > estradiol > progesterone. PIAS1 binding to full-length human AR in a reversed yeast two hybrid system was also androgen dependent. [35S] PIAS1 bound a glutathione S-transferase-AR-DNA binding domain (amino acids 544-634) fusion protein in affinity matrix assays. In transient cotransfection assays using CV1 cells with full-length human AR and a mouse mammary tumor virus luciferase reporter vector, there was an androgen-dependent 3- to 5-fold greater increase in luciferase activity with PIAS1 over that obtained with an equal amount of control antisense cDNA or mutant PIAS1. Constitutive transcriptional activity of the AR N-terminal+DNA binding domain was increased 6-fold by PIAS1. PIAS1 also enhanced glucocorticoid receptor transactivation in response to dexamethasone but inhibited progesterone-induced progesterone receptor transactivation in the same assay system. mRNA for PIAS1 was highly expressed in testis of human, monkey, rat, and mouse. In rat testis the onset of PIAS1 mRNA expression coincided with the initiation of spermatogenesis between 25-30 days of age. Immunostaining of human and mouse testis with PIAS1-specific antiserum demonstrated coexpression of PIAS1 with AR in Sertoli cells and Leydig cells. In addition, PIAS1 was expressed in spermatogenic cells. The results suggest that PIAS1 functions in testis as a nuclear receptor transcriptional coregulator and may have a role in AR initiation and maintenance of spermatogenesis.
Mol Endocrinol 2000 Jan
PMID:Protein inhibitor of activated STAT-1 (signal transducer and activator of transcription-1) is a nuclear receptor coregulator expressed in human testis. 1062 44

A tobacco MAP kinase termed SIPK (Salicylic acid-Induced Protein Kinase) is activated in response to a variety of stress signals, including pathogen attack and wounding (S. Zhang and D.F. Klessig, Proc. Natl. Acad. Sci. USA 95:7225-7230, 1998; S. Zhang and D.F. Klessig, Proc. Natl. Acad. Sci. USA 95:7433-7438, 1998). Using the yeast two-hybrid system, we have identified a gene encoding a protein that interacts with SIPK but not the wounding induced protein kinase (WIPK), which is another tobacco MAP kinase. Sequence analysis indicated that this SIPK-interacting protein is a member of the MAP kinase kinase family; thus, it was named SIPK kinase (SIPKK). Co-immunoprecipitation experiments demonstrated that SIPKK and SIPK interact in vitro. Consistent with its putative function as a kinase, SIPKK phosphorylated myelin basic protein in vitro. Interestingly, SIPKK was induced at the mRNA level after Tobacco mosaic virus (TMV) infection or wounding, albeit with kinetics that are too slow to account for the activation of SIPK following these stimuli.
Mol Plant Microbe Interact 2000 Jan
PMID:Molecular cloning and characterization of a tobacco MAP kinase kinase that interacts with SIPK. 1065 93

Accumulating evidence suggests that phosphatases play an important role in regulating a variety of signal transduction pathways that have a bearing on cancer. The kinase-associated phosphatase (KAP) is a human dual-specificity protein phosphatase that was identified as a Cdc2- or Cdk2-interacting protein by a yeast two-hybrid screening, yet the biological significance of these interactions remains elusive. We have identified the KAP gene as an overexpressed gene in breast and prostate cancer by using a phosphatase domain-specific differential-display PCR strategy. Here we report that breast and prostate malignancies are associated with high levels of KAP expression. The sublocalization of KAP is variable. In normal cells, KAP is primarily found in the perinuclear region, but in tumor cells, a significant portion of KAP is found in the cytoplasm. Blocking KAP expression by antisense KAP in a tetracycline-regulatable system results in a reduced population of S-phase cells and reduced Cdk2 kinase activity. Furthermore, lowering KAP expression led to inhibition of the transformed phenotype, with reduced anchorage-independent growth and tumorigenic potential in athymic nude mice. These findings suggest that therapeutic intervention might be aimed at repression of KAP gene overexpression in human breast and prostate cancer.
Mol Cell Biol 2000 Mar
PMID:Overexpression of kinase-associated phosphatase (KAP) in breast and prostate cancer and inhibition of the transformed phenotype by antisense KAP expression. 3251 51

PML fuses with retinoic acid receptor alpha (RARalpha) in the t(15;17) translocation that causes acute promyelocytic leukemia (APL). In addition to localizing diffusely throughout the nucleoplasm, PML mainly resides in discrete nuclear structures known as PML oncogenic domains (PODs), which are disrupted in APL and spinocellular ataxia cells. We isolated the Fas-binding protein Daxx as a PML-interacting protein in a yeast two-hybrid screen. Biochemical and immunofluorescence analyses reveal that Daxx is a nuclear protein that interacts and colocalizes with PML in the PODs. Reporter gene assay shows that Daxx drastically represses basal transcription, likely by recruiting histone deacetylases. PML, but not its oncogenic fusion PML-RARalpha, inhibits the repressor function of Daxx. In addition, SUMO-1 modification of PML is required for sequestration of Daxx to the PODs and for efficient inhibition of Daxx-mediated transcriptional repression. Consistently, Daxx is found at condensed chromatin in cells that lack PML. These data suggest that Daxx is a novel nuclear protein bearing transcriptional repressor activity that may be regulated by interaction with PML.
Mol Cell Biol 2000 Mar
PMID:Sequestration and inhibition of Daxx-mediated transcriptional repression by PML. 1066 54

The PRL receptor (PRL-R) signals through the Janus tyrosine kinases (JAK) and other non-JAK tyrosine kinases, some of which are preassociated with the PRL-R. To clone PRL-R interacting proteins, the intracellular domain (ICD) of the long form of the PRL-R was used in a yeast two-hybrid screen of a human B cell cDNA library. One PRL-R interacting protein was identified as the 42-kDa form of the enzyme 2',5'-oligoadenylate synthetase (OAS). The in vivo interactions in yeast were further confirmed by an in vitro interaction assay and by coimmunoprecipitation in transfected mammalian cells. Functionally, OAS reduced the basal activity of two types of promoters in transiently transfected COS-1 cells. In the presence of PRL, OAS inhibited PRL induction of the immediate early IRF-1 (interferon-regulatory factor 1) promoter, but not PRL induction of the differentiation-specific beta-casein promoter, suggesting that OAS exerts specific effects on immediate early gene promoters. The inhibitory effects of OAS were accompanied by a reduction in PRL-inducible Stat1 (signal transducer and activator of transcription 1) DNA binding activity at the IRF-1 GAS (interferon-gamma-activated sequence) element. These results demonstrate a novel interaction of OAS with the PRL-R and suggest a role for OAS in modulating Stat1-mediated signaling to an immediate early gene promoter. Although previously characterized as a regulator of ribonuclease (RNase) L antiviral responses, OAS may have additional effects on cytokine receptor signal transduction pathways.
Mol Endocrinol 2000 Feb
PMID:Association of 2',5'-oligoadenylate synthetase with the prolactin (PRL) receptor: alteration in PRL-inducible stat1 (signal transducer and activator of transcription 1) signaling to the IRF-1 (interferon-regulatory factor 1) promoter. 1067 1

Aip3p/Bud6p is a regulator of cell and cytoskeletal polarity in Saccharomyces cerevisiae that was previously identified as an actin-interacting protein. Actin-interacting protein 3 (Aip3p) localizes at the cell cortex where cytoskeleton assembly must be achieved to execute polarized cell growth, and deletion of AIP3 causes gross defects in cell and cytoskeletal polarity. We have discovered that Aip3p localization is mediated by the secretory pathway. Mutations in early- or late-acting components of the secretory apparatus lead to Aip3p mislocalization. Biochemical data show that a pool of Aip3p is associated with post-Golgi secretory vesicles. An investigation of the sequences within Aip3p necessary for Aip3p localization has identified a sequence within the N terminus of Aip3p that is sufficient for directing Aip3p localization. Replacement of the N terminus of Aip3p with a homologous region from a Schizosaccharomyces pombe protein allows for normal Aip3p localization, indicating that the secretory pathway-mediated Aip3p localization pathway is conserved. Delivery of Aip3p also requires the type V myosin motor Myo2p and its regulatory light-chain calmodulin. These data suggest that one function of calmodulin is to activate Myo2p's activity in the secretory pathway; this function is likely the polarized movement of late secretory vesicles and associated Aip3p on actin cables.
Mol Biol Cell 2000 Feb
PMID:The secretory pathway mediates localization of the cell polarity regulator Aip3p/Bud6p. 1067 21

Pho85 is a cyclin-dependent protein kinase (Cdk) in budding yeast with roles in cell metabolism and cell cycle progression. Activation of Pho85 occurs through association with Pho85 cyclins (Pcls), of which 10 are known. When complexed with the G1 cyclins, Pcl1 and Pcl2, Pho85 is required for cell cycle progression in the absence of the Cdc28-dependent cyclins, Cln1 and Cln2. To identify potential targets of Pcl2-Pho85, we performed a two-hybrid screen using the Pcl2 cyclin as bait and recovered the transcription factor Swi5 as a Pcl2-interacting protein. We performed both biochemical and genetic tests to discover the biological significance of the interaction between Pcl2 and Swi5 seen in the two-hybrid assay. We found that Swi5 interacts in vitro with Pho85 cyclins and is phosphorylated in vitro by the Pho80-Pho85 kinase. We discovered that a subset of genes that are controlled by Swi5 and a homologous transcription factor, Ace2, was misregulated in a pho85 deletion strain; expression of the ASH1 and CTS1 genes was reduced in an ace2 deletion strain, whereas expression of both genes was increased in an ace2Delta pho85Delta double mutant. We also found that overexpression of SWI5 caused cell lethality in a pho85 deletion strain. Our results are consistent with misregulation of Swi5 activity in vivo in the absence of Pho85 and implicate Swi5 as a potential substrate of Pho85 cyclin-dependent kinase complexes.
Mol Microbiol 2000 Feb
PMID:Interactions between Pho85 cyclin-dependent kinase complexes and the Swi5 transcription factor in budding yeast. 1069 59


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