期刊
MOLECULAR AND CELLULAR BIOCHEMISTRY
卷 319, 期 1-2, 页码 153-161出版社
SPRINGER
DOI: 10.1007/s11010-008-9888-0
关键词
5-Aminolevulinic acid synthase 1 (ALAS1); Heme; Cobalt protoporphyrin (CoPP); Huh-7 cells; HepG2 cells; mRNA stability; Protein stability
类别
资金
- United States Public Health Service [RO1-DK38825, NO-1 DK92326, UO-1 DK065193]
- Center for Vascular Biology, University of Connecticut Health Center, Farmington, CT
- Carolinas Medical Center, Charlotte, NC
- Yale Center for Medical Informatics, New Haven, CT
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [R01DK038825, N01DK092326, U01DK065193] Funding Source: NIH RePORTER
5-Aminolevulinic acid synthase 1 (ALAS1) is the first and rate-controlling enzyme of heme biosynthesis. This study was to determine the effects of heme and selected nonheme metalloporphyrins on human ALAS1 gene expression in hepatocytes. We found that, upon heme and cobalt protoporphyrin (CoPP) treatments, ALAS1 mRNA levels were down-regulated significantly by ca. 50% or more. Measurement of mRNA in the presence of actinomycin D showed that these down-regulations were due to the decreases in mRNA half-lives. Furthermore, the levels of mitochondrial mature ALAS1 protein were down-regulated by 60-70%, but those of the cytosolic precursor protein were up-regulated by 2-5-fold. Measurement of protein in the presence of cycloheximide (CHX) suggests that elevation of the precursor form is due to the increase in protein half-lives. These results provide novel insights into the mechanisms of heme repressional effects on ALAS1 and provide a rationale for further investigation of CoPP as a therapeutic agent for acute porphyric syndromes.
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