Downregulation of constitutive and heavy metal-induced metallothionein-I expression by nuclear factor I

被引:25
作者
Majumder, S
Ghoshal, K
Gronostajski, RM
Jacob, ST
机构
[1] Ohio State Univ, Coll Med, Dept Mol & Cellular Biochem, Columbus, OH 43210 USA
[2] Cleveland Clin Fdn, Lerner Res Inst, Dept Canc Biol, Cleveland, OH 44195 USA
来源
GENE EXPRESSION | 2001年 / 9卷 / 4-5期
关键词
nuclear factor I (NFI); metallothionein; metal transcription factor-I (MTF-I);
D O I
10.3727/000000001783992588
中图分类号
Q81 [生物工程学(生物技术)]; Q93 [微生物学];
学科分类号
071005 ; 0836 ; 090102 ; 100705 ;
摘要
Although the existence of repressor protein(s) involved in the regulation of highly inducible metallothionein-1 (MT-I) gene expression has been postulated, none has been identified to date. We considered nuclear factor I (NFI) protein as a potential repressor, as three half-sites for NFI binding are present on MT-I promoter and NT;I is known to downregulate several cellular gene promoters. Overexpression of all four isoforms of mouse NFI protein (NFI-A, -B, -C, and -X) suppressed both constitutive and heavy metal-induced activation of the MT-I promoter in HepG2 cells. However, unlike other target genes of NFI, direct interaction of NFI with MT-I promoter is not necessary to mediate its repression. Point mutation of the NFI binding sites within the MT-I promoter that abrogates NFI binding in vitro could not alleviate the repression. Similarly, NFI proteins also repress activity of minimal MT-I promoter deficient in the NFI binding sites. Further, an NFI-C deletion mutant lacking the DNA binding domain continued to repress MT-I promoter. Overexpression of MTF-I, the key transacting factor involved in MT-I gene transcription, surmounted NFI-mediated repression of the basal and zinc-induced MT-I promoter activity. These data demonstrate that NFI is a repressor of MT-I expression, where its DNA binding activity is not essential to downregulate the MT-I promoter. Interaction of NFI with another protein(s), probably MTF-I, may be involved in this repression.
引用
收藏
页码:203 / 215
页数:13
相关论文
共 54 条
[1]  
ADAMAS AD, 1995, J BIOL CHEM, V270, P19668
[2]   NF1-L IS THE DNA-BINDING COMPONENT OF THE PROTEIN COMPLEX AT THE PERIPHERIN NEGATIVE REGULATORY ELEMENT [J].
ADAMS, AD ;
CHOATE, DM ;
THOMPSON, MA .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1995, 270 (12) :6975-6983
[3]  
AIYAR A, 1993, BIOTECHNIQUES, V14, P366
[4]  
ALAM J, 1992, J BIOL CHEM, V267, P16379
[5]   Regulation of metallothionein gene expression by oxidative stress and metal ions [J].
Andrews, GK .
BIOCHEMICAL PHARMACOLOGY, 2000, 59 (01) :95-104
[6]   Purification and characterization of a rat liver protein that recognizes CCAAT-homologous sequences of the metallothionein promoter and trans-activates this promoter [J].
Aniskovitch, LP ;
Jacob, ST .
ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS, 1997, 341 (02) :337-346
[7]  
BARCHURSKI CJ, 1997, J BIOL CHEM, V272, P32759
[8]   Methylation-induced repression - Belts, braces, and chromatin [J].
Bird, AP ;
Wolffe, AP .
CELL, 1999, 99 (05) :451-454
[9]   Nuclear factor I-mediated repression of the mouse mammary tumor virus promoter is abrogated by the coactivators p300/CBP and SRC-1 [J].
Chaudhry, AZ ;
Vitullo, AD ;
Gronostajski, RM .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1999, 274 (11) :7072-7081
[10]   Nuclear factor I (NFI) isoforms differentially activate simple versus complex NFI-responsive promoters [J].
Chaudhry, AZ ;
Vitullo, AD ;
Gronostajski, RM .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1998, 273 (29) :18538-18546