Metal-responsive transcription factor 1 (MTF-1) 2 is a zinc finger protein that regulates gene expressions in response to various stresses, such as heavy metal exposure (1), oxidative stress (2), and hypoxia (3). MTF-1 genes have been identified in many species from insects to mammals, and encode proteins with high amino acid identities (4 -6). The N-terminal region of MTF-1 has six Cys 2 -His 2 -type zinc finger motifs that specifically bind to metal responsive elements (MREs) at the promoters of target genes. Three other distinct domains (an acidic, a proline-rich, and a serine/threonine-rich) on MTF-1 are responsible for the transactivation activity of the protein (7,8).Metallothioneins (MTs) are the most extensively studied target genes of MTF-1 (7). MTs are low molecular weight, cysteine-rich proteins that play important roles in zinc homeostasis and heavy metal detoxification (9). MTF-1 is responsible for the basal and metal-induced expression of MT genes (10). In addition, MTF-1 regulates the expression of zinc transporter-1 (11), ␥-glutamyl-cysteine synthetase heavy chain (12), and placental growth factor (13). It also plays a critical role in embryonic development because disruption of the Mtf-1 gene in mouse leads to oxidative damage-derived impairment of hepatocytic development and fetal lethality (12).MTF-1 resides mainly in the cytoplasm. Upon metal exposure or stress induction, MTF-1 translocates into the nucleus and binds to MREs (14,15). Several factors, such as USF-1, USF-2, NF-B, and HIF-1␣, can modulate the transcriptional activity of . Histone acetyltransferase p300/ CBP and transcription factor Sp1 can rapidly form a complex with MTF-1 upon zinc treatment and stimulate gene transcription (20). Alternatively, zinc and cadmium activate MTF-1 by phosphorylating MTF-1 through different kinase cascades. The exact mechanism of the modifications remains unknown (21-23).Post-translational modification of proteins by small ubiquitin-like modifier (SUMO) has emerged as an important regulatory mechanism of cellular processes (24). Among the three major SUMO isoforms identified in mammalian cells, SUMO-1 is the best characterized isoform. SUMO-1 and ubiquitin have only 18% sequence identity but share similar structural folds (25). Comparable with ubiquitination, SUMO conjugates covalently to substrates via a specific enzymatic cascade, including the heterodimeric SUMO-activating enzyme SAE1/SAE2 (E1), the SUMO-conjugating enzyme Ubc9 (E2), and in some cases, the SUMO E3 ligases (26). Sumoylation of proteins occurs mostly on lysine residues with a ⌿KXE (where ⌿ is a bulky hydrophobic residue and X is any amino acid) sequence and the modification can be dynamically reversed by the sentrin/SUMO-specific proteases (SENPs) (27). In contrast to the ubiquitination of proteins for degradation, the functional consequences of protein sumoylation are diverse. Sumoylation * This work was supported by Grant NSC98-2311-B-007-015-MY3 from the National Science Council, Taiwan, Republic of China. □ S The on-line version...
