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Section: Genetics » Regulation of Gene Expression » Mechanisms in Eukaryotes
 
 
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  Cell surface receptors in cholesterol metabolism and drug production
 
     
 
Content
⇒ Regulation of Gene Expression 3. A Variety of Mechanisms in Eukaryotes
⇒ Regulation at Transcription Level
⇒ Activation of transcription
⇒ Britten-Davidson model for unit of transcription
⇒ Gene battery
⇒ Chromosomal proteins and gene expression
⇒ Repression of transcription 
⇒ Specific DNA sequences controlling transcription
⇒ Transgenic plants to study regulatory sequences
⇒ Modification of DNA sequences and their transcripts in gene expression
⇒ Alternative splicing of transcripts
⇒ Regulation at translation level
⇒ Activation and repression of translation
⇒ Masked mRNA in eggs of sea urchin and Xenopus
⇒ Regulation by gene re-arrangement
⇒ Expression of immunoglobulin genes
⇒ Yeast mating type switching
⇒ Trypanosome surface antigen (VSG) switching
⇒ Synthesis of mRNA in pieces in VSG genes in trypanosome
⇒ Regulation by reversible phosphorylation
⇒ Signal transduction and second messengers
⇒ Proteins and peptide hormones and gene expression
⇒ Steroid hormones and gene expression
⇒ Interferon stimulated gene expression (without a second messenger)
⇒ Cell surface receptors in cholesterol metabolism and drug production
⇒ Ubiquitin protein and regulation of heat shock genes
Cell surface receptors in cholesterol metabolism and drug production (1985, '88 Nobel Prizes)
During the last more than a decade, a study of regulation of cholesterol metabolism was conducted by S. Brown and J.L. Goldstein (at University of Texas, U.S.A.), both of them sharing the Nobel Prize for Physiology and Medicine in 1985. Their study mainly involved the study of cell surface receptor for low density lipoprotein (LDL), which is a major transporter of blood cholesterol from blood to the interior of fibroblast and liver cells.

The receptor molecule forms a complex with LDL and enters the cell through pinocytosis. The receptor is recycled and LDL is degraded so that cholesterol can be utilized in the cell. When a patient has a defective gene for receptor, it leads to high blood cholesterol and LDL. This leads to the development of familial hypercholesterol-aemia or coronary atherosclerosis (before the age of 20 in a homozygous defective). Brown and Goldstein also synthesized the gene for enzyme HMGCoA reductase, which is responsible for cholesterol synthesis and is under the control of a feedback inhibition. These researches may eventually lead to prevention and treatment of atherosclerosis.

J. W. Black, G. B. Elion and G.H.Hitchings (winners of Nobel Prize in Physiology/Medicine, 1988) conducted a detailed study on the principles involved in drug designing. Through these studies, they were able to develop drugs for treating "cancer", "gout", "malaria" and viral infections such as "herpes". They found that there are drugs like "6-mercaptopurine" and "thioguanine" which inhibit DNA synthesis leading to inhibition of cell division and therefore are effective in cancer chemotherapy. Another drug developed by them is "azathioprine" used to fight transplant rejection, or diseases like rhematoid arthritis; in both cases the drug acts by attacking the immune system (immunosuppressive effect).

Elion and Hitchings also studied the differences in nucleic acid synthesis of prokaryotes and human cells, which led to the development of drugs like "pyramethamine" for malaria, "trimethoprim" for bacterial infection and "acyclovir" for herpes virus infection. Azidothymidine (AZT) developed recently for AIDS also works on the principle formulated by Elion and Hitchings.
 
     






     
     
 
 
     
 
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