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Distinct transcriptional regulation and function of the human BACE2 and BACE1 genes.
FASEB J. 2005 May; 19(7):739-49.FJ

Abstract

Amyloid beta protein (Abeta) is the principal component of neuritic plaques in Alzheimer's disease (AD). Abeta is derived from beta amyloid precursor protein (APP) by beta- and gamma-secretases. Beta-site APP cleaving enzyme 1 (BACE1) has been identified as the major beta-secretase. BACE2 is the homolog of BACE1. The BACE2 gene is on chromosome 21 and has been implicated in the pathogenesis of AD. However, the function of BACE2 in Abeta generation is controversial. Some studies have shown that BACE2 cleaved APP at the beta-site whereas other studies showed it cleaved around the alpha-secretase site. To elucidate the involvement of BACE2 in AD pathogenesis, we compared BACE2 and BACE1 gene regulation and their functions in Abeta generation. We cloned and functionally characterized the human BACE2 promoter. The BACE2 gene is controlled by a TATA-less promoter. Though Sp1 can regulate both BACE1 and BACE2 genes, comparative sequence analysis and transcription factor prediction showed little similarity between the two promoters. BACE1 increased APP cleavage at the beta-site and Abeta production whereas BACE2 did not. Overexpression of BACE2 significantly increased sAPP levels in conditioned media but markedly reduced Abeta production. Knockdown of BACE2 resulted in increased APP C83. Our data indicate that despite being homologous in amino acid sequence, BACE2 and BACE1 have distinct functions and transcriptional regulation. BACE2 is not a beta-secretase, but processes APP within the Abeta domain at a site downstream of the alpha-secretase cleavage site. Our data argue against BACE2 being involved in the formation of neuritic plaques in AD.

Authors+Show Affiliations

Department of Psychiatry, Brain Research Center, The University of British Columbia, Vancouver, BC, Canada.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

15857888

Citation

Sun, Xiulian, et al. "Distinct Transcriptional Regulation and Function of the Human BACE2 and BACE1 Genes." FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology, vol. 19, no. 7, 2005, pp. 739-49.
Sun X, Wang Y, Qing H, et al. Distinct transcriptional regulation and function of the human BACE2 and BACE1 genes. FASEB J. 2005;19(7):739-49.
Sun, X., Wang, Y., Qing, H., Christensen, M. A., Liu, Y., Zhou, W., Tong, Y., Xiao, C., Huang, Y., Zhang, S., Liu, X., & Song, W. (2005). Distinct transcriptional regulation and function of the human BACE2 and BACE1 genes. FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology, 19(7), 739-49.
Sun X, et al. Distinct Transcriptional Regulation and Function of the Human BACE2 and BACE1 Genes. FASEB J. 2005;19(7):739-49. PubMed PMID: 15857888.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Distinct transcriptional regulation and function of the human BACE2 and BACE1 genes. AU - Sun,Xiulian, AU - Wang,Yingcheng, AU - Qing,Hong, AU - Christensen,Michelle A, AU - Liu,Yunqiang, AU - Zhou,Weihui, AU - Tong,Yigang, AU - Xiao,Cuiying, AU - Huang,Yi, AU - Zhang,Sizhong, AU - Liu,Xiehe, AU - Song,Weihong, PY - 2005/4/29/pubmed PY - 2005/12/24/medline PY - 2005/4/29/entrez SP - 739 EP - 49 JF - FASEB journal : official publication of the Federation of American Societies for Experimental Biology JO - FASEB J VL - 19 IS - 7 N2 - Amyloid beta protein (Abeta) is the principal component of neuritic plaques in Alzheimer's disease (AD). Abeta is derived from beta amyloid precursor protein (APP) by beta- and gamma-secretases. Beta-site APP cleaving enzyme 1 (BACE1) has been identified as the major beta-secretase. BACE2 is the homolog of BACE1. The BACE2 gene is on chromosome 21 and has been implicated in the pathogenesis of AD. However, the function of BACE2 in Abeta generation is controversial. Some studies have shown that BACE2 cleaved APP at the beta-site whereas other studies showed it cleaved around the alpha-secretase site. To elucidate the involvement of BACE2 in AD pathogenesis, we compared BACE2 and BACE1 gene regulation and their functions in Abeta generation. We cloned and functionally characterized the human BACE2 promoter. The BACE2 gene is controlled by a TATA-less promoter. Though Sp1 can regulate both BACE1 and BACE2 genes, comparative sequence analysis and transcription factor prediction showed little similarity between the two promoters. BACE1 increased APP cleavage at the beta-site and Abeta production whereas BACE2 did not. Overexpression of BACE2 significantly increased sAPP levels in conditioned media but markedly reduced Abeta production. Knockdown of BACE2 resulted in increased APP C83. Our data indicate that despite being homologous in amino acid sequence, BACE2 and BACE1 have distinct functions and transcriptional regulation. BACE2 is not a beta-secretase, but processes APP within the Abeta domain at a site downstream of the alpha-secretase cleavage site. Our data argue against BACE2 being involved in the formation of neuritic plaques in AD. SN - 1530-6860 UR - https://www.unboundmedicine.com/medline/citation/15857888/Distinct_transcriptional_regulation_and_function_of_the_human_BACE2_and_BACE1_genes_ L2 - https://doi.org/10.1096/fj.04-3426com DB - PRIME DP - Unbound Medicine ER -