The Recessive Phenotype Displayed by a Dominant Negative Microphthalmia-Associated Transcription Factor Mutant Is a Result of Impaired Nuclear Localization Potential

Takebayashi, Kimiko; Chida, Kazuhiro; Tsukamoto, I; Morii, Eiichi; Munakata, Hiroshi; Arnheiter, Heinz; Kuroki, Tamotsu; Kitamura, Yukihiko; Nomura, Shosaku

doi:10.1128/mcb.16.3.1203

Cited by 114 publications

(89 citation statements)

References 53 publications

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“…One approach was the use of cotransfection assays and in vitro DNA binding assays, whereas the other approach utilized the available mouse models that harbor different genetic mutations in MITF. In 1996, Kitamura and his colleagues (6) demonstrated that the MITF protein in mi/mi mice is mainly located in the cytoplasm, and therefore they proposed that the presence of the mutated protein can lead to cellular defect by anchoring MITF hetrodimerization partners in the cytoplasm. MITF regulates the expression of mouse mast cell protease (mMCP)-6 (7), mMCP-5 (8) c-kit (9), p75 nerve growth factor (8), granzyme B (10), tryptophan hydroxylase (11), and cathepsin K (12).…”

Section: The Microphthalmia Transcription Factor (Mitf)mentioning

confidence: 99%

A New Role for the STAT3 Inhibitor, PIAS3

Levy

Nechushtan

Razin

2002

Journal of Biological Chemistry

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In vitro and in vivo evidence suggest that microphthalmia transcription factor (MITF) plays a key regulatory role in tissue-specific gene regulation in several cell types, including melanocytes, osteoclasts, and mast cells. A yeast two-hybrid search, using a portion of a nonmutated MITF gene as the bait in the screening of a mast cell library, resulted in the isolation of the STAT3 inhibitor, PIAS3. PIAS3 is a transcriptional inhibitor that acts by specifically inhibiting STAT3's DNA binding activity. We found that it can directly associate with MITF using an in vitro pull-down assay. Immunoprecipitation of MITF from rat basophilic leukemic cells or mouse melanocytes resulted in the specific co-immunoprecipitation of PIAS3. Co-transfection of MITF with PIAS3 in NIH 3T3 fibroblasts containing an mMCP-6 promoter-luciferase reporter demonstrated up to 94% inhibition of MITF-mediated transcriptional activation. Using a gel-shift assay, it was shown that PIAS3 can block DNA binding activity. It was also found that STAT3 does not interfere, either in vitro or in vivo, with the interaction between PIAS3 and MITF. These data suggest that PIAS3 functions in vivo as a key molecule in supressing the transcriptional activity of MITF, a role of considerable importance in mast cell and melanocyte development.

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Section: The Microphthalmia Transcription Factor (Mitf)mentioning

confidence: 99%

A New Role for the STAT3 Inhibitor, PIAS3

Levy

Nechushtan

Razin

2002

Journal of Biological Chemistry

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“…39,40 A retroviral vector, pM5Gneo, 41 a derivative of myeloproliferative sarcoma virus vector, was a kind gift from Dr. W. Ostertag (Universitä t Hamburg, Hamburg, Germany). The purified SmaI-HincII fragment from pBS-ϩ-MITF or pBS-mi-MITF was introduced into the blunted EcoRI site of pM5Gneo.…”

Section: Construction Of Retrovirus Vector and Its Infectionmentioning

confidence: 99%

“…39,40 Oligonucleotides were labeled with ␣-[ 32 P]dCTP by filling 5Ј-overhangs, and were used as probes for EGMSA. DNA binding assays were performed in a 20 l reaction mixture containing 10 mmol/L Tris-HCl (pH 8.0), 1 mmol/L ethylenediaminetetraacetic acid, 75 mmol/L KCl, 1 mmol/L dithiothreitol, 4% Ficoll type 400, 50 ng poly (dI-dC), 25 ng of the labeled DNA probe, and 3.5 g of GST-ϩ-MITF or GST-mi-MITF fusion protein.…”

Section: Electrophoretic Gel Mobility Shift Assay (Egmsa)mentioning

confidence: 99%

Independent Influence of Strain Difference and mi Transcription Factor on the Expression of Mouse Mast Cell Chymases

Jippo

Lee

et al. 2001

The American Journal of Pathology

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Expression of mouse mast cell protease (mMCP) genes was examined with particular attention to the transactivation effect of mi transcription factor (MITF) and the expression differences between C57BL/6 (B6) and WB strains. We had reported the enhancing effect of MITF on the expression of mMCP-4, -5, and -6 genes in cultured mast cells (CMCs) of B6 strain, and in the present study we demonstrated the enhancing effect on the expression of mMCP-2 and -9 genes as well. The enhancing effect of MITF on the expression of mMCP-2, -4, -5, -6, and -9 genes was also detected in CMCs of the WB strain. The regulation of mMCP-2, -4, and -9 genes was localized to a specific promoter element (CANNTG) which was recognized and bound by MITF and which was conserved between the B6 and WB strains. On the other hand, the expression of mMCP-2, -4, and -9 genes was smaller in CMCs of the B6 strain when compared to their expression in CMCs of the WB strain. Although mMCP-5 is a chymase as mMCP-2, -4, and -9, and genes encoding all of the chymases are located on chromosome 14, the mMCP-5 gene was regulated in a manner distinct from mMCP-2, -4, and -9 genes. Mast cells of mice contain various proteases. The complementary (c)DNAs and genes that encode mast cell carboxypeptidase A and nine of the 10 mouse mast cell-specific serine proteases have been cloned and sequenced. [1][2][3][4][5][6][7][8][9][10][11] The mast cell carboxypeptidase A is an exopeptidase that prefers C-terminal aliphatic amino acids. The mouse mast cell proteases (mMCPs) -1, -2, -4, -5, and -9 are predicted to be chymases from the deduced amino acid sequences, whereas mMCP-6, -7, and transmembrane tryptase to be tryptases. The mMCP-1, -2, -4, -5, and -9 genes reside on chromosome 14 and link with a gene complex encoding blood cell proteases, such as the cathepsin G and multiple granzymes. [11][12][13][14][15] On the other hand, the mast cell carboxypeptidase A gene resides on the chromosome 3, and the mMCP-6, -7, and transmembrane tryptase genes reside on the chromosome 17. 12 Chromosomal localization of mMCP-8 has not been reported. From the viewpoint of structure, mMCP-8 is more closely related to cathepsin G and granzymes than to mast cell chymases. 10 The protease expression phenotype is influenced not only by extracellular environmental factors 16 -19 but also by intracellular factors. 20 -22 As extracellular factors, effects of tissue environments and cytokines have been studied. Messenger RNA (mRNA) of mMCP-2 is expressed by mast cells in the mucosal layer of the stomach of (WB ϫ C57BL6) F 1 (hereafter called WBB6F 1 )-ϩ/ϩ mice but not by mast cells in the muscle layer of the stomach. 16 Addition of interleukin 9, interleukin 10, or transforming growth factor-␤ 1 significantly increased the mRNA expression of both mMCP-1 and -2 in cultured mast cells (CMCs). 9,17,18 On the other hand, addition of stem cell factor increased the expression of mMCP-4 and -6 in CMCs. 19 Transcription factors that are involved in the transactivation of mMCP genes are intracellular f...

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“…The MITF encoded by the mutant mi allele deletes 1 of 4 consecutive arginines in the basic domain (hereafter mi-MITF) (Hodgkinson et al, 1993;Hemesath et al, 1994;Steingrimsson et al, 1994). The mi-MITF is defective in the DNA binding activity and the nuclear localization potential, and it does not transactivate target genes Takebayashi et al, 1996;Tsujimura et al, 1996;Jippo et al, 1997;Ito et al, 1998;Kim et al, 1998). The mi/mi mice show microphthalmia, depletion of pigment in both hair and eyes, osteopetrosis, and decrease of mast cells (Silvers, 1979;Green, 1981;Stevens and Loutit, 1982;Stechschulte et al, 1987).…”

Section: Introductionmentioning

confidence: 99%

Synergy of PEBP2/CBF with mi transcription factor (MITF) for transactivation of mouse mast cell protease 6 gene

et al. 1999

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The mi locus encodes a member of the basic ± helix ± loop ± helix ± leucine zipper (bHLH-Zip) protein family of transcription factors (hereafter called MITF). Although the bHLH-Zip family transcription factors generally recognize and bind CANNTG motifs, the expression of mouse mast cell protease 6 (MMCP-6) gene is regulated by MITF through the GACCTG motif in the promoter region. The GACCTG motif was partly overlapped the TGTGGTC sequence, which was bound by polyomavirus enhancer binding protein 2 (PEBP2). In the present study, the eect of PEBP2 on the expression of MMCP-6 gene was examined. PEBP2 that is composed of a and b subunits was expressed by mast cell lines and cultured mast cells derived from spleen. The overexpression of dominant negative PEBP2 cDNA reduced the expression of MMCP-6. Moreover, the simultaneous transfection of the plasmid containing MITF cDNA and the plasmid containing PEBP2 cDNA increased the MMCP-6 promoter activity. For the synergistic action of PEBP2 and MITF, the intact GACCTG and TGTGGTC motifs were prerequisite. The PEBP2aB1 mutant which lacked the region downstream from the Runt domain did not bind MITF and lost the synergistic function. These results indicated that PEBP2 and MITF synergistically transactivated the MMCP-6 gene and that the region downstream from the Runt domain of PEBP2aB1 was essential for the physical and functional interactions with MITF.

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The Recessive Phenotype Displayed by a Dominant Negative Microphthalmia-Associated Transcription Factor Mutant Is a Result of Impaired Nuclear Localization Potential

Cited by 114 publications

References 53 publications

A New Role for the STAT3 Inhibitor, PIAS3

A New Role for the STAT3 Inhibitor, PIAS3

Independent Influence of Strain Difference and mi Transcription Factor on the Expression of Mouse Mast Cell Chymases

Synergy of PEBP2/CBF with mi transcription factor (MITF) for transactivation of mouse mast cell protease 6 gene

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