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rdf:type |
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lifeskim:mentions |
umls-concept:C0007600,
umls-concept:C0015219,
umls-concept:C0021920,
umls-concept:C0031437,
umls-concept:C0033684,
umls-concept:C0034987,
umls-concept:C0035820,
umls-concept:C0038323,
umls-concept:C0205171,
umls-concept:C1167622,
umls-concept:C1511695
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pubmed:issue |
20
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pubmed:dateCreated |
1995-6-12
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pubmed:databankReference |
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pubmed:abstractText |
The cholesterol analogue 25-hydroxycholesterol kills animal cells by blocking the proteolytic activation of two sterol-regulated transcription factors designated sterol regulatory element binding protein-1 and -2 (SREBP-1 and SREBP-2). These proteins, each approximately 1150 amino acids in length, are embedded in the membranes of the nucleus and endoplasmic reticulum by virtue of hydrophobic COOH-terminal segments. In cholesterol-depleted cells the proteins are cleaved to release soluble NH2-terminal fragments of approximately 480 amino acids that enter the nucleus and activate genes encoding the low density lipoprotein receptor and enzymes of cholesterol synthesis. 25-Hydroxycholesterol blocks this cleavage, and cells die of cholesterol deprivation. We previously described a mutant 25-hydroxycholesterol-resistant hamster cell line (SRD-1 cells) in which the SREBP-2 gene had undergone a recombination between the intron following codon 460 and an intron in an unrelated gene. The SREBP-2 sequence terminated at residue 460, eliminating the membrane attachment domain and producing a constitutively active factor that no longer required proteolysis and thus was not inhibited by 25-hydroxycholesterol. Here, we report that two additional sterol-resistant cell lines (SRD-2 and SRD-3) have also undergone genomic rearrangements in the intron following codon 460 of the SREBP-2 gene. Although the molecular rearrangements differ in the three mutant lines, each leads to the production of a constitutively active transcription factor whose SREBP-2 sequence terminates at residue 460. These findings provide a dramatic illustration of the advantage that introns provide in allowing proteins to gain new functions in response to new environmental challenges.
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pubmed:grant |
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/25-hydroxycholesterol,
http://linkedlifedata.com/resource/pubmed/chemical/Antigens, Nuclear,
http://linkedlifedata.com/resource/pubmed/chemical/CCAAT-Enhancer-Binding Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/DNA Helicases,
http://linkedlifedata.com/resource/pubmed/chemical/DNA-Binding Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Hydroxycholesterols,
http://linkedlifedata.com/resource/pubmed/chemical/Ku autoantigen,
http://linkedlifedata.com/resource/pubmed/chemical/Nuclear Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/RNA, Messenger,
http://linkedlifedata.com/resource/pubmed/chemical/Recombinant Fusion Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Sterol Regulatory Element Binding...,
http://linkedlifedata.com/resource/pubmed/chemical/Sterol Regulatory Element Binding...,
http://linkedlifedata.com/resource/pubmed/chemical/Transcription Factors,
http://linkedlifedata.com/resource/pubmed/chemical/XRCC5 protein, human
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pubmed:status |
MEDLINE
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pubmed:month |
May
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pubmed:issn |
0021-9258
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pubmed:author |
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pubmed:issnType |
Print
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pubmed:day |
19
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pubmed:volume |
270
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
12152-61
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pubmed:dateRevised |
2008-11-21
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pubmed:meshHeading |
pubmed-meshheading:7744865-Amino Acid Sequence,
pubmed-meshheading:7744865-Animals,
pubmed-meshheading:7744865-Antigens, Nuclear,
pubmed-meshheading:7744865-Base Sequence,
pubmed-meshheading:7744865-Biological Transport,
pubmed-meshheading:7744865-CCAAT-Enhancer-Binding Proteins,
pubmed-meshheading:7744865-CHO Cells,
pubmed-meshheading:7744865-Cell Line,
pubmed-meshheading:7744865-Cell Nucleus,
pubmed-meshheading:7744865-Cricetinae,
pubmed-meshheading:7744865-Cricetulus,
pubmed-meshheading:7744865-DNA Helicases,
pubmed-meshheading:7744865-DNA-Binding Proteins,
pubmed-meshheading:7744865-Drug Resistance,
pubmed-meshheading:7744865-Fibroblasts,
pubmed-meshheading:7744865-Genes,
pubmed-meshheading:7744865-Helix-Loop-Helix Motifs,
pubmed-meshheading:7744865-Hydroxycholesterols,
pubmed-meshheading:7744865-Introns,
pubmed-meshheading:7744865-Lung,
pubmed-meshheading:7744865-Molecular Sequence Data,
pubmed-meshheading:7744865-Mutagenesis,
pubmed-meshheading:7744865-Nuclear Proteins,
pubmed-meshheading:7744865-Polymerase Chain Reaction,
pubmed-meshheading:7744865-RNA, Messenger,
pubmed-meshheading:7744865-RNA Splicing,
pubmed-meshheading:7744865-Recombinant Fusion Proteins,
pubmed-meshheading:7744865-Sequence Alignment,
pubmed-meshheading:7744865-Sequence Homology, Nucleic Acid,
pubmed-meshheading:7744865-Sterol Regulatory Element Binding Protein 1,
pubmed-meshheading:7744865-Sterol Regulatory Element Binding Protein 2,
pubmed-meshheading:7744865-Transcription Factors,
pubmed-meshheading:7744865-Transcriptional Activation
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pubmed:year |
1995
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pubmed:articleTitle |
Three different rearrangements in a single intron truncate sterol regulatory element binding protein-2 and produce sterol-resistant phenotype in three cell lines. Role of introns in protein evolution.
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pubmed:affiliation |
Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas 75235, USA.
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pubmed:publicationType |
Journal Article,
Comparative Study,
Research Support, U.S. Gov't, P.H.S.,
Research Support, Non-U.S. Gov't
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