期刊
MOLECULAR AND CELLULAR BIOLOGY
卷 21, 期 9, 页码 3220-3233出版社
AMER SOC MICROBIOLOGY
DOI: 10.1128/MCB.21.9.3220-3233.2001
关键词
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资金
- NCI NIH HHS [R01 CA027607, CA27607] Funding Source: Medline
- NEI NIH HHS [EY03040, P30 EY003040] Funding Source: Medline
- NIAID NIH HHS [R01 AI045150, AI45150, R56 AI045150] Funding Source: Medline
When mammalian cells are subjected to stress targeted to the endoplasmic reticulum (ER), such as depletion of the ER Ca2+ store, the transcription of a family of glucose regulated protein (GRP) genes encoding ER chaperones is induced. The GRP promoters contain multiple copies of the ER stress response element (ERSE), consisting of a unique tripartite structure, CCAAT(N-9)CCACG. Within a subset of mammalian ERSEs, N-9 represents a GC-rich sequence of 9 bp that is conserved across species. A novel complex (termed ERSF) exhibits enhanced binding to the ERSE of the grp78 and ERp72 promoters using HeLa nuclear extracts prepared from ER-stressed cells. Optimal binding of ERSF to ERSE and maximal ERSE mediated stress inducibility require the conserved GGC motif within the 9 bp region. Through chromatographic purification and subsequent microsequencing, we have identified ERSF as TFII-I. Whereas TFII-I remains predominantly nuclear in both nontreated NIH 3T3 cells and cells treated with thapsigargin (Tg), a potent inducer of the GRP stress response through depletion of the ER Ca2+ store, the level of TFII-I transcript was elevated in Tg-stressed cells, correlating with an increase in TFII-I protein level in the nuclei of Tg -stressed cells. Purified recombinant TFII-I isoforms bind directly to the ERSEs of grp78 and ERp72 promoters. The stimulation of ERSE-mediated transcription by TFII-I requires the consensus tyrosine phosphorylation site of TFII-I and the GGC sequence motif of the ERSE, We further discovered that TFII-I is an interactive protein partner of ATF6 and that optimal stimulation of ERSE by ATF6 requires TFII-I.
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