TY - JOUR
T1 - Sterol-regulated release of SREBP-2 from cell membranes requires two sequential cleavages, one within a transmembrane segment
AU - Sakai, Juro
AU - Duncan, Elizabeth A.
AU - Rawson, Robert B.
AU - Hua, Xianxin
AU - Brown, Michael S.
AU - Goldstein, Joseph L.
N1 - Funding Information:
We thank Drs. T. Y. Chang and M. T. Hasan for providing M19 cells, Gloria Brunschede, Fang Shen, and Georgeanna Cantrell for excellent technical assistance, Jacqueline Le and Lisa Beatty for invaluable help with tissue culture, and Jeff Cormier and Michelle Laremore for synthesis of oligonucleotides and DNA sequencing. This research was supported by grants from the National Institutes of Health (HL20948) and the Perot Family Foundation. E. A. D. is supported by Medical Scientists Training Grant GM08014.
PY - 1996/6/28
Y1 - 1996/6/28
N2 - Sterol regulatory element binding proteins (SREBPs) are transcription factors attached to the endoplasmic reticulum. The NH2-segment, which activates transcription, is connected to membranes by a hairpin anchor formed by two transmembrane sequences and a short lumenal loop. Using H-Ras-SREBP-2 fusion proteins, we show that the NH2-segment is released from membranes by two sequential cleavages. The first, regulated by sterols, occurs in the lumenal loop. The second, not regulated by sterols, occurs within the first transmembrane domain. The liberated NH2-segment enters the nucleus and activates genes controlling cholesterol synthesis and uptake. Certain mutant Chinese hamster ovary cells are auxotrophic for cholesterol because they fail to carry out the second cleavage; the NH2-segment remains membrane-bound and transcription is not activated.
AB - Sterol regulatory element binding proteins (SREBPs) are transcription factors attached to the endoplasmic reticulum. The NH2-segment, which activates transcription, is connected to membranes by a hairpin anchor formed by two transmembrane sequences and a short lumenal loop. Using H-Ras-SREBP-2 fusion proteins, we show that the NH2-segment is released from membranes by two sequential cleavages. The first, regulated by sterols, occurs in the lumenal loop. The second, not regulated by sterols, occurs within the first transmembrane domain. The liberated NH2-segment enters the nucleus and activates genes controlling cholesterol synthesis and uptake. Certain mutant Chinese hamster ovary cells are auxotrophic for cholesterol because they fail to carry out the second cleavage; the NH2-segment remains membrane-bound and transcription is not activated.
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U2 - 10.1016/S0092-8674(00)81304-5
DO - 10.1016/S0092-8674(00)81304-5
M3 - Article
C2 - 8674110
AN - SCOPUS:0030604717
SN - 0092-8674
VL - 85
SP - 1037
EP - 1046
JO - Cell
JF - Cell
IS - 7
ER -