title: Upstream stimulatory factors 1 and 2 mediate the transcription of angiotensin II binding and inhibitory protein.
abstract: The angiotensin II type 1 receptor (AT1R)-associated protein (ATRAP/Agtrap) promotes constitutive internalization of the AT1R so as to specifically inhibit the pathological activation of its downstream signaling yet preserve the base-line physiological signaling activity of the AT1R. Thus, tissue-specific regulation of Agtrap expression is relevant to the pathophysiology of cardiovascular and renal disease. However, the regulatory mechanism of Agtrap gene expression has not yet been fully elucidated. In this study, we show that the proximal promoter region from -150 to +72 of the mouse Agtrap promoter, which contains the X-box, E-box, and GC-box consensus motifs, is able to elicit substantial transcription of the Agtrap gene. Among these binding motifs, we showed that the E-box specifically binds upstream stimulatory factor (Usf) 1 and Usf2, which are known E-box-binding transcription factors. It is indicated that the E-box-Usf1/Usf2 binding regulates Agtrap expression because of the following: 1) mutation of the E-box to prevent Usf1/Usf2 binding reduces Agtrap promoter activity; 2) knockdown of Usf1 or Usf2 affects both endogenous Agtrap mRNA and Agtrap protein expression, and 3) the decrease in Agtrap mRNA expression in the afflicted kidney by unilateral ureteral obstruction is accompanied by changes in Usf1 and Usf2 mRNA. Furthermore, the results of siRNA transfection in mouse distal convoluted tubule cells and those of unilateral ureteral obstruction in the afflicted mouse kidney suggest that Usf1 decreases but Usf2 increases the Agtrap gene expression by binding to the E-box. The results also demonstrate a functional E-box-USF1/USF2 interaction in the human AGTRAP promoter, thereby suggesting that a strategy of modulating the E-box-USF1/USF2 binding has novel therapeutic potential.
authors: Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, USA.
authors: Miyuki
authors: M
authors: Matsuda
authors: Kouichi
authors: K
authors: Tamura
authors: Hiromichi
authors: H
authors: Wakui
authors: Akinobu
authors: A
authors: Maeda
authors: Masato
authors: M
authors: Ohsawa
authors: Tomohiko
authors: T
authors: Kanaoka
authors: Kengo
authors: K
authors: Azushima
authors: Kazushi
authors: K
authors: Uneda
authors: Sona
authors: S
authors: Haku
authors: Yuko
authors: Y
authors: Tsurumi-Ikeya
authors: Yoshiyuki
authors: Y
authors: Toya
authors: Yohei
authors: Y
authors: Maeshima
authors: Akio
authors: A
authors: Yamashita
authors: Satoshi
authors: S
authors: Umemura
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000378:metabolism; D000804:Angiotensin II / Q000378:metabolism*; D000818:Animals; D001483:Base Sequence; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D034741:RNA, Small Interfering / Q000378:metabolism; D012084:Renin-Angiotensin System; D014158:Transcription, Genetic; D051720:Upstream Stimulatory Factors / Q000378:metabolism*
chemical_list: C449676:AGTRAP protein, human; D048868:Adaptor Proteins, Signal Transducing; C119712:Agtrap protein, mouse; D034741:RNA, Small Interfering; C497181:USF1 protein, human; C497184:USF2 protein, human; D051720:Upstream Stimulatory Factors; C497183:Usf1 protein, mouse; C497186:Usf2 protein, mouse; D000804:Angiotensin II
keywords: Angiotensin; Distal Tubule; Gene Transcription; Receptors; Renin Angiotensin System; Transcription Regulation
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