Binding of THZif-1, a MAZ-like Zinc Finger Protein to the Nuclease-hypersensitive Element in the Promoter Region of the c-MYC Protooncogene

Sakatsume, Osamu; Tsutsui, Hatsumi; Wang, Yifei; Gao, Hui; Tang, Xiaoou; Yamauchi, Taeko; Murata, Takehide; Itakura, Keiichi; Yokoyama, Kazunari K.

doi:10.1074/jbc.271.49.31322

Cited by 40 publications

(22 citation statements)

References 70 publications

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“…1, 9, and 10). The nuclease hypersensitivity element (NHE) III 1 of the c-MYC promoter controls 85-90% of c-MYC transcription and has been the subject of considerable research over the past two decades (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21). Originally identified as a major site of DNase I hypersensitivity (13), the NHE III 1 is a 27-bp sequence located Ϫ142 to Ϫ115 bp upstream from the P1 promoter (Fig.…”

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confidence: 99%

RETRACTED: Mutations in the G-quadruplex silencer element and their relationship to c-MYC overexpression, NM23 repression, and therapeutic rescue

Grand

Powell

Nagle

et al. 2004

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

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We have demonstrated that a parallel G-quadruplex structure in the c-MYC promoter functions as a transcriptional repressor element. Furthermore, a specific G-to-A mutation in this element results in destabilization of the G-quadruplex repressor element and an increase in basal transcriptional activity. To validate this model in an in vivo context, we have examined the sequence of this region in human colorectal tumors and the surrounding normal tissue. We have found that ≈30% of tumors contain one of two specific G-to-A mutations, not present in the surrounding normal tissue, that destabilize the parallel G-quadruplex, which would be expected to give rise to abnormally high expression of c-MYC in these cells. In contrast, G-quadruplex-disruptive mutations were absent in 20 colon adenomas, suggesting that these mutations occur late in tumorigenesis. We have also demonstrated that these same mutations are found in established colorectal cell lines. NM23-H2 levels are lower in cancer tissues and cell lines that harbor these mutations. In cells with repressed levels of NM23-H2, the mutated and destabilized G-quadruplex silencer element can be reinstated by the addition of G-quadruplex-stabilizing compounds, providing an opportunity for therapeutic intervention for patients carrying these mutations

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confidence: 99%

RETRACTED: Mutations in the G-quadruplex silencer element and their relationship to c-MYC overexpression, NM23 repression, and therapeutic rescue

Grand

Powell

Nagle

et al. 2004

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

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“…As suggested by its name, this protein regulates c-myc gene expression by providing both stimulatory (Komatsu et al, 1997) and inhibitory controls (Izzo et al, 1999). In most cases, however, the family of MAZ proteins (Logan et al, 1993;Sakatsume et al, 1996) activates gene promoters, including the SCL/TAL-1 promoter (Bockamp et al, 1995), the serotonin 1a receptor promoter (Parks and Shenk, 1996), the adenovirus major late promoter (Parks and Shenk, 1997), and the CD4 promoter (Duncan et al, 1995). The present studies show that MAZ also activates the rat PNMT gene promoter.…”

Section: Discussionmentioning

confidence: 99%

Regulation of the Rat PhenylethanolamineN-Methyltransferase Gene by Transcription Factors Sp1 and MAZ

Her¹,

Claycomb²,

Tai³

et al. 2003

Mol Pharmacol

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The rat phenylethanolamine N-methyltransferase (PNMT) gene promoter contains 1-base pair (bp) overlapping consensus sequences for Sp1 and MAZ transcription factors at Ϫ48 and Ϫ38 bp, respectively. Gel mobility assays using PC-12-derived RS1 cell nuclear extracts or in vitro translated proteins showed that Sp1 and MAZ specifically bind to these elements, that MAZ displaces/prevents Sp1 binding, and that Sp1 and MAZ binding is mutually exclusive, with occupancy dependent on each factor's concentration and affinity for its consensus element. In transfection assays, PNMT promoter activation by Sp1 and MAZ depends on promoter length, with Ϫ893 bp of sequence yielding greatest activation. Although MAZ has higher affinity for its binding element, it is a less effective activator. Changes in PNMT promoter activity for the constructs pGL3RP60 or pGL3RP893 using a fixed amount of MAZ expression construct and a variable amount of Sp1 expression construct or vice versa confirmed the latter. Mutation of the MAZ or Sp1 sites in pGL3RP60 attenuated but did not eliminate PNMT promoter activity, even though the proteins no longer bind to their consensus elements. Phosphatase treatment of RS1 cell nuclear extracts prevented MAZ-and Sp1-DNA binding complex formation. Although MAZ and Sp1 elevate endogenous PNMT mRNA in RS1 cells, MAZ preferentially increases intron-retaining whereas Sp1 preferentially increases intronless mRNA. Thus, expression of the PNMT gene seems to be modulated through competitive binding of phosphorylated Sp1 and MAZ to their consensus elements in the promoter. In addition, posttranscriptional regulation seems to be another important mechanism controlling PNMT expression.

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“…MAZi (99.3% amino acid identity to human MAZ) was discovered in human pancreatic islet cells and shown to recognize both single-and double-stranded DNA (65). While THZif-1 has 98.2% amino acid similarity to MAZ, it contains a variant second zinc finger (only 33.3% similar to MAZ) and is capable of binding single-stranded, double-stranded, and triple-helical DNA (35,54). Interestingly, MAZR and MAZi appear to activate, whereas THZif-1 represses, expression of c-myc.…”

Section: Discussionmentioning

confidence: 99%

Quantitative Proteomic Identification of MAZ as a Transcriptional Regulator of Muscle-Specific Genes in Skeletal and Cardiac Myocytes

Himeda

Ranish

Hauschka

2008

Molecular and Cellular Biology

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We identified a conserved sequence within the Muscle creatine kinase (MCK) promoter that is critical for high-level activity in skeletal and cardiac myocytes (MCK Promoter Element X [MPEX]). After selectively enriching for MPEX-binding factor(s) (MPEX-BFs), ICAT-based quantitative proteomics was used to identify MPEX-BF candidates, one of which was MAZ (Myc-associated zinc finger protein). MAZ transactivates the MCK promoter and binds the MPEX site in vitro, and chromatin immunoprecipitation analysis demonstrates enrichment of MAZ at the endogenous MCK promoter and other muscle gene promoters (Skeletal ␣-actin, Desmin, and ␣-Myosin heavy chain) in skeletal and cardiac myocytes. Consistent with its role in muscle gene transcription, MAZ transcripts and DNA-binding activity are upregulated during skeletal myocyte differentiation. Furthermore, MAZ was shown to bind numerous sequences (e.g., CTCCTCCC and CTCCACCC) that diverge from the GA box binding motif. Alternate motifs were identified in many muscle promoters, including Myogenin and MEF2C, and one motif was shown to be critical for Six4 promoter activity in both skeletal and cardiac myocytes. Interestingly, MAZ occupies and is able to transactivate the Six4 promoter in skeletal but not cardiac myocytes. Taken together, these findings are consistent with a previously unrecognized role for MAZ in muscle gene regulation.The mouse Muscle creatine kinase (MCK) gene serves as a useful model for understanding muscle-specific gene transcription since its expression is restricted to terminally differentiated striated muscle, where it is one of the most abundantly expressed genes. Transcription of MCK is regulated by an upstream enhancer (Ϫ1256 to Ϫ1050), a proximal promoter (Ϫ358 to ϩ7), and an intron 1 modulatory region (ϩ740 to ϩ1731). The upstream enhancer confers muscle-specific expression to reporter constructs in cell culture, transgenic mice, and virus-mediated gene transfer (1,13,24,30,31,56,61) and contains at least seven control elements, which were identified by footprinting, deletion/mutation analysis, and gel mobility shift assays (1,8,16,39,41). The sequences and relative positions of elements in the MCK enhancer (CArG/SRE, AP2, MEF3, A/T-rich, left and right E-boxes, and MEF2) are highly conserved between mammalian species, and many of the associated transcription factors have been identified (11,19,20,27,39,68).In contrast to the upstream enhancer, very little is known about the highly conserved (Ϫ358 to ϩ7) region comprising the MCK proximal promoter. Studies with cultured cells and transgenic mice have demonstrated that the MCK promoter alone is capable of driving muscle-specific expression (30,56) and that it is ϳ40-fold more active in skeletal than in cardiac myocytes (C. L. Himeda and S. D. Hauschka, unpublished data). However, the MCK promoter also synergizes with the upstream enhancer to drive much higher expression of reporter constructs in both types of striated muscle (13,56). The MCK promoter is known to contain a highly conserved E-box and CA...

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Binding of THZif-1, a MAZ-like Zinc Finger Protein to the Nuclease-hypersensitive Element in the Promoter Region of the c-MYC Protooncogene

Cited by 40 publications

References 70 publications

RETRACTED: Mutations in the G-quadruplex silencer element and their relationship to c-MYC overexpression, NM23 repression, and therapeutic rescue

RETRACTED: Mutations in the G-quadruplex silencer element and their relationship to c-MYC overexpression, NM23 repression, and therapeutic rescue

Regulation of the Rat PhenylethanolamineN-Methyltransferase Gene by Transcription Factors Sp1 and MAZ

Quantitative Proteomic Identification of MAZ as a Transcriptional Regulator of Muscle-Specific Genes in Skeletal and Cardiac Myocytes

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