Molecular Genetics

X.D. Wang, R. Sato, M.S. Brown, X.X. Hua, J.L. Goldstein, "Srebp-1, a membrane-bound transcription factor released by sterol-regulated proteolysis," Cell, 77:53-62, 1994. (Cited in more than 65 publications as of February 1996) Comments by Joseph L. Goldstein, University of Texas Southwestern Medical Center SURPRISED: Joseph Goldstein investigates cholesterol control. The work reported in this paper reveals the mechanism for transcriptional control of the genes that regulate cholesterol in cells and in the bloodstream. For years, Joseph L. Goldstein, chairman and professor of molecular genetics at the University of Texas Southwestern Medical Center in Dallas, and his University of Texas medical center colleague Michael Brown, the Paul J. Thomas Professor of Genetics and director of the Jonsson Center for Molecular Genetics, have studied certain cholesterol-regulating proteins, including the low-density lipid (LDL) protein receptor. LDL is the major molecule that controls blood cholesterol. Its receptor is encoded by one of the genes regulated by the transcription factor, Srebp-1. "The paper describes a proteolytic pathway for activating a transcription factor that is bound to the membrane," explains Goldstein, who shared the 1985 Nobel Prize in physiology or medicine with Brown for their cholesterol research. The transcription factor was very difficult to purify. "We now know why-it's an integral protein embedded in the membranes of the endoplasmic reticulum and the nuclear envelope," he notes. "Only a small part of the protein moves to the nucleus. The protein was difficult to find because we didn't know where to look. "This work shows how the cholesterol gene transcription factor is activated," Goldstein says. "When the cell is depleted of cholesterol, the membrane-bound transcription factor is cleaved proteolytically to release the first 500 amino acids, which contain the DNA-binding element. It travels to the nucleus and activates the transcription of genes encoding enzymes of cholesterol synthesis and the gene for the LDL receptor, which is involved in cholesterol uptake. As a result, the cell takes up and synthesizes cholesterol. When cholesterol accumulates in the cell, the proteolytic cleavage is suppressed-it's a feedback system." NOBEL PURSUIT: Michael Brown continues his prize-winning research The researchers also discovered that the transcription factor has a peculiar shape: a hairpin loop that anchors it in two places to the cell membrane. "The sequence revealed that the protein had 500 amino acids that faced the cytoplasm, and there was a hairpin loop of two membrane segments plus a short sequence anchoring the protein in the membrane. Another 500-amino-acid sequence comes out and also faces that cytoplasm. The U of the hairpin is embedded in the membrane. "The first half of the molecule looks like other basic helix-loop-helix transcription factors," he says. "It seems that nature made the first half to look like ordinary transcription factors, but then added this hairpin and a long carboxyl-terminal extension, which has a unique sequence. We don't know the function of that extension yet." Goldstein suspects that this particular transcription factor and the mechanisms of controlling cholesterol synthesis evolved because cholesterol is an essential component of the cell membrane. "It was a very surprising finding," he says. "Since then we have demonstrated biochemically that it [the transcription factor] is a membrane protein anchored in this hairpin orientation," he remarks. "Now we're trying to figure out how this proteolysis occurs. It turns out to be complicated and to involve several steps." Goldstein comments that the work provides further insights into how cells control cholesterol. Understanding the process might help explain why some individuals are more prone to higher cholesterol levels than others are, and may aid in developing improved cholesterol-regulating drugs. Several previous papers contributed to this work, Goldstein points out. For example, the classic work for which they shared the Nobel-describing the cholesterol control pathway-appears in M.S. Brown and J.L. Goldstein, Science, 232:34-47, 1986. Another paper, X. Wang et al., Journal of Biological Chemistry, 268:14497-504, 1993, describes the biochemical purification of Srebp-1. The cDNA cloning of Srebp-1 is outlined in C. Yokoyama et al., Cell, 75:187-97, 1993.

Molecular Genetics

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