SREBP-1, a membrane-bound transcription factor released by sterol-regulated proteolysis.
Sterol regulatory element-binding protein 1 (SREBP-1), a member of the basic-helix-loop-helix-leucine zipper (bHLH-ZIP) family of transcription factors, is synthesized as a 125 kd precursor that is attached to the nuclear envelope and endoplasmic reticulum. In sterol-depleted cells, the membrane-bound precursor is cleaved to generate a soluble NH2-terminal fragment (apparent molecular mass, 68 kd) that translocates to the nucleus. This fragment, which includes the bHLH-ZIP domain, activates transcription of the genes for the LDL receptor and HMG CoA synthase. Sterols inhibit the cleavage of SREBP-1, and the 68 kd nuclear form is rapidly catabolized, thereby reducing transcription. ALLN, an inhibitor of neutral cysteine proteases, blocks the breakdown of the 68 kd form and superinduces sterol-regulated genes. Sterol-regulated proteolysis of a membrane-bound transcription factor provides a novel mechanism by which transcription can be regulated by membrane lipids.
Wang
X
X
Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas 75235.
Sato
R
R
Brown
M S
MS
Hua
X
X
Goldstein
J L
JL
D000595:Amino Acid Sequence; D022762:CCAAT-Enhancer-Binding Proteins; D002451:Cell Compartmentation / Q000187:drug effects; D002467:Cell Nucleus / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism*; D005786:Gene Expression Regulation; D006367:HeLa Cells; D006801:Humans; D007425:Intracellular Membranes / Q000378:metabolism; D008563:Membrane Lipids / Q000378:metabolism; D008565:Membrane Proteins / Q000737:chemistry / Q000378:metabolism; D008969:Molecular Sequence Data; D008970:Molecular Weight; D009687:Nuclear Proteins / Q000737:chemistry / Q000378:metabolism*; D011498:Protein Precursors / Q000378:metabolism; D051780:Sterol Regulatory Element Binding Protein 1; D013261:Sterols / Q000494:pharmacology*; D014157:Transcription Factors / Q000378:metabolism*
D022762:CCAAT-Enhancer-Binding Proteins; D004268:DNA-Binding Proteins; D008563:Membrane Lipids; D008565:Membrane Proteins; D009687:Nuclear Proteins; D011498:Protein Precursors; C497387:SREBF1 protein, human; D051780:Sterol Regulatory Element Binding Protein 1; D013261:Sterols; D014157:Transcription Factors