GENES: STRUCTURE AND REGULATION
Identification of ERSE-II, a New cis-Acting Element Responsible for the ATF6-dependent Mammalian Unfolded Protein Response*

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Herp is a 54-kDa membrane protein in the endoplasmic reticulum (ER). The mRNA expression level of Herp is increased by the accumulation of unfolded proteins in the ER. Transcriptional changes designed to deal with this type of ER stress is called the unfolded protein response (UPR). Most mammalian UPR-target genes encode ER-resident molecular chaperones: GRP78, GRP94, and calreticulin. The promoter regions of these genes contain acis-acting ER stress response element, ERSE, with the consensus sequence of CCAAT-N9-CCACG. Under conditions of ER stress, p50ATF6 (the active form of the transcription factor, ATF6) binds to CCACG when CCAAT is bound by the general transcription factor, NF-Y/CBF. Here, we report the genomic structure of human Herp and the presence of a new ER stress response element, ERSE-II, in its promoter region. The gene for Herp consists of eight exons, localized to chromosome 16q12.2–13. The promoter region contains a single ERSE-like sequence. In reporter gene assays, disruption of thiscis-element resulted in a partial reduction of the transcriptional response to ER stress, suggesting that the element is functional for the UPR. These results also suggest the involvement of additional elements in the UPR. Further analysis, using an optimized plasmid containing an mRNA-destabilizing sequence, revealed ERSE-II (ATTGG-N-CCACG) as the second ER stress response element. Interestingly, ERSE-II was also dependent on p50ATF6, in a manner similar to that of ERSE, despite the disparate structure. The strong induction of Herp mRNA by ER stress would be achieved by the cooperation of ERSE and ERSE-II.

AB034990

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Published, JBC Papers in Press, December 8, 2000, DOI 10.1074/jbc.M010486200

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This work was supported in part by grants-in-aid from the Ministry of Health and Welfare of Japan; from the Ministry of Education, Science, Sports, and Culture of Japan; from the Japan Society for the Promotion of Science; and by the Program for Promotion of Fundamental Studies in Health Sciences of the Organization for Pharmaceutical Safety and Research of Japan.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The nucleotide sequence reported in this paper has been submitted to the GenBank™/EMBL/DDBJ Data Bank with accession number .