The ‘PINIT’ motif, of a newly identified conserved domain of the PIAS protein family, is essential for nuclear retention of PIAS3L

Duval, David Timothy; Duval, G.; Kédinger, Claude; Poch, Olivier; Bœuf, Hélène

doi:10.1016/s0014-5793(03)01116-5

Cited by 74 publications

(78 citation statements)

References 33 publications

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“…mPIAS3 was amplified from plasmids p513-flag-mPIAS3-wild-type and p513-flag-mPIAS3L-wild-type (22) kindly provided by Hélène Boeuf (Université Bordeaux, Bordeaux, France) using specific primers. To generate the NH 2 -and COOHterminal fragments primers, 5′-aaacatatggtgatgagtttccg-3′ and 5′-aaactcgagcatgagtgacacccggag-3′, or 5′-aaacatatgtgcccgctagggaagatg-3′ and 5′-aaactcgaggtccagggaaatgatgtc-3′ were used, respectively.…”

Section: Plasmid Constructionmentioning

confidence: 99%

The Intracellular Delivery of a Recombinant Peptide Derived from the Acidic Domain of PIAS3 Inhibits STAT3 Transactivation and Induces Tumor Cell Death

Borghouts

Tittmann

Delis

et al. 2010

Molecular Cancer Research

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Signaling components, which confer an "addiction" phenotype on cancer cells, represent promising drug targets. The transcription factor signal transducers and activators of transcription 3 (STAT3) is constitutively activated in many different types of tumor cells and its activity is indispensible in a large fraction. We found that the expression of the endogenous inhibitor of STAT3, protein inhibitor of activated STAT3 (PIAS3), positively correlates with STAT3 activation in normal cells. This suggests that PIAS3 controls the extent and the duration of STAT3 activity in normal cells and thus prevents its oncogenic function. In cancer cells, however, the expression of PIAS3 is posttranscriptionally suppressed, possibly enhancing the oncogenic effects of activated STAT3. We delimited the interacting domains of STAT3 and PIAS3 and identified a short fragment of the COOH-terminal acidic region of PIAS3, which binds strongly to the coiled-coil domain of STAT3. This PIAS3 fragment was used to derive the recombinant STAT3-specific inhibitor rPP-C8. The addition of a protein transduction domain allowed the efficient internalization of rPP-C8 into cancer cells. This resulted in the suppression of STAT3 target gene expression, in the inhibition of migration and proliferation, and in the induction of apoptosis at low concentrations [half maximal effective concentration (EC 50 ), <3 μmol/L]. rPP-C8 did not affect normal fibroblasts and represents an interesting lead for the development of novel cancer drugs targeting the coiled-coil domain of STAT3. Mol Cancer Res; 8(4); 539-53. ©2010 AACR.

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Section: Plasmid Constructionmentioning

confidence: 99%

The Intracellular Delivery of a Recombinant Peptide Derived from the Acidic Domain of PIAS3 Inhibits STAT3 Transactivation and Induces Tumor Cell Death

Borghouts

Tittmann

Delis

et al. 2010

Molecular Cancer Research

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“…The LXXLL signature motif has been shown to mediate interactions between nuclear receptors and their co-regulators [23]. The Pro-Ile-Asn-Ile-Thr (PINIT) motif represents a highly conserved region of PIAS proteins, which may be involved in the nuclear retention of PIAS3 [24]. A highly acidic region (AD) is also conserved in the PIAS family.…”

Section: Pias In Gene Regulation 198mentioning

confidence: 99%

Regulation of cytokine signaling pathways by PIAS proteins

2006

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Cytokines activate multiple signal transduction pathways to regulate gene expression. STATs and NF-kB are two important families of transcription factors activated by cytokines. Abnormal regulation of STAT and NF-kB activities has been associated with human diseases. The protein inhibitor of activated STAT (PIAS) protein family has been proposed to interact with over 60 proteins, many of which are transcription factors involved in the immune system. PIAS proteins regulate transcription through several mechanisms, including blocking the DNA-binding activity of transcription factors, recruiting transcriptional co-repressors and promoting protein sumoylation. This article is to review the role of PIAS proteins in the regulation of STAT and NF-kB signaling pathways.

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“…6A). These findings demonstrate that PRMT1-mediated The N-terminal SAP box (Saf-A/B, Acinus, PIAS) is required for DNA-binding, PINIT motif is involved in nuclear retention of certain family members, RING finger-like domain is essential for Sumo ligase activity and the acidic domain is important for protein-protein interactions (Duval et al 2003;Shuai and Liu 2005). (E) His-tagged PIAS1 deletion constructs were purified from E. coli, and equal amounts were used for in vitro methylation with recombinant GST-PRMT1 in the presence of methyl-14 C-labeled SAM.…”

Section: R E T R a C T E Dmentioning

confidence: 84%

PRMT1-mediated arginine methylation of PIAS1 regulates STAT1 signaling

Weber¹,

Maass²,

Schuemann³

et al. 2009

Genes Dev.

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To elucidate the function of the transcriptional coregulator PRMT1 (protein arginine methyltranferase 1) in interferon (IFN) signaling, we investigated the expression of STAT1 (signal transducer and activator of transcription) target genes in PRMT1-depleted cells. We show here that PRMT1 represses a subset of IFNginducible STAT1 target genes in a methyltransferase-dependent manner. These genes are also regulated by the STAT1 inhibitor PIAS1 (protein inhibitor of activated STAT1). PIAS1 is arginine methylated by PRMT1 in vitro as well as in vivo upon IFN treatment. Mutational and mass spectrometric analysis of PIAS1 identifies Arg 303 as the single methylation site. Using both methylation-deficient and methylation-mimicking mutants, we find that arginine methylation of PIAS1 is essential for the repressive function of PRMT1 in IFN-dependent transcription and for the recruitment of PIAS1 to STAT1 target gene promoters in the late phase of the IFN response. Methylation-dependent promoter recruitment of PIAS1 results in the release of STAT1 and coincides with the decline of STAT1-activated transcription. Accordingly, knockdown of PRMT1 or PIAS1 enhances the antiproliferative effect of IFNg. Our findings identify PRMT1 as a novel and crucial negative regulator of STAT1 activation that controls PIAS1-mediated repression by arginine methylation.[Keywords: Transcriptional repression; interferon signaling; STAT1; PIAS1; PRMT1; arginine methylation] Supplemental material is available at http://www.genesdev.org.

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The ‘PINIT’ motif, of a newly identified conserved domain of the PIAS protein family, is essential for nuclear retention of PIAS3L

Cited by 74 publications

References 33 publications

The Intracellular Delivery of a Recombinant Peptide Derived from the Acidic Domain of PIAS3 Inhibits STAT3 Transactivation and Induces Tumor Cell Death

The Intracellular Delivery of a Recombinant Peptide Derived from the Acidic Domain of PIAS3 Inhibits STAT3 Transactivation and Induces Tumor Cell Death

Regulation of cytokine signaling pathways by PIAS proteins

PRMT1-mediated arginine methylation of PIAS1 regulates STAT1 signaling

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