Identification of argininosuccinate lyase as a hypoxia-responsive gene in rat hepatocytes. 2000

M U Latasa, and M V Carretero, and E R García-Trevijano, and L Torres, and J M Mato, and M A Avila
Unidad de Hepatologia y Terapia Génica, Departamento de Medicina Interna, Facultad de Medicina, Universidad de Navarra, Pamplona, Spain.

OBJECTIVE The differential oxygenation of periportal and perivenous hepatocytes has been demonstrated as a major determinant in the zonated expression of certain metabolic pathways in the liver. We have searched for novel genes whose expression could be modulated by hypoxia in cultured rat hepatocytes. METHODS Primary cultures of rat hepatocytes were incubated under normoxic (21% oxygen) or hypoxic (3% oxygen) conditions for 6 h. Differences in gene expression under both conditions were analyzed using the technique of differential display by means of PCR. RESULTS We have identified the enzyme argininosuccinate lyase (ASL) as being downregulated by hypoxia. ASL is a cytosolic protein which participates in urea metabolism. ASL expression was time-dependently reduced in hypoxia. Hypoxia modulated the responses of this gene to the two main hormonal signals which induce ASL mRNA: glucocorticoids and cAMP. ASL mRNA levels decreased in response to ATP-reducing agents. CoCl2 mimicked the effect of hypoxia, suggesting the implication of a hemoprotein in this response. Hypoxia did not affect ASL mRNA stability, indicating that this effect occurs at the transcriptional level. CONCLUSIONS Our observations suggest that differences in oxygen levels across the hepatic parenchyma could participate in the zonated expression of ASL.

UI MeSH Term Description Entries
D008297 Male Males
D005576 Colforsin Potent activator of the adenylate cyclase system and the biosynthesis of cyclic AMP. From the plant COLEUS FORSKOHLII. Has antihypertensive, positive inotropic, platelet aggregation inhibitory, and smooth muscle relaxant activities; also lowers intraocular pressure and promotes release of hormones from the pituitary gland. Coleonol,Forskolin,N,N-Dimethyl-beta-alanine-5-(acetyloxy)-3-ethenyldodecahydro-10,10b-dihydroxy-3,4a,7,7,10a-pentamethyl-1-oxo-1H-naphtho(2,1-b)pyran-6-yl Ester HCl,NKH 477,NKH-477,NKH477
D000255 Adenosine Triphosphate An adenine nucleotide containing three phosphate groups esterified to the sugar moiety. In addition to its crucial roles in metabolism adenosine triphosphate is a neurotransmitter. ATP,Adenosine Triphosphate, Calcium Salt,Adenosine Triphosphate, Chromium Salt,Adenosine Triphosphate, Magnesium Salt,Adenosine Triphosphate, Manganese Salt,Adenylpyrophosphate,CaATP,CrATP,Manganese Adenosine Triphosphate,MgATP,MnATP,ATP-MgCl2,Adenosine Triphosphate, Chromium Ammonium Salt,Adenosine Triphosphate, Magnesium Chloride,Atriphos,Chromium Adenosine Triphosphate,Cr(H2O)4 ATP,Magnesium Adenosine Triphosphate,Striadyne,ATP MgCl2
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D001123 Argininosuccinate Lyase An enzyme of the urea cycle which splits argininosuccinate to fumarate plus arginine. Its absence leads to the metabolic disease ARGININOSUCCINIC ACIDURIA in man. EC 4.3.2.1. Argininosuccinase,Lyase, Argininosuccinate
D012333 RNA, Messenger RNA sequences that serve as templates for protein synthesis. Bacterial mRNAs are generally primary transcripts in that they do not require post-transcriptional processing. Eukaryotic mRNA is synthesized in the nucleus and must be exported to the cytoplasm for translation. Most eukaryotic mRNAs have a sequence of polyadenylic acid at the 3' end, referred to as the poly(A) tail. The function of this tail is not known for certain, but it may play a role in the export of mature mRNA from the nucleus as well as in helping stabilize some mRNA molecules by retarding their degradation in the cytoplasm. Messenger RNA,Messenger RNA, Polyadenylated,Poly(A) Tail,Poly(A)+ RNA,Poly(A)+ mRNA,RNA, Messenger, Polyadenylated,RNA, Polyadenylated,mRNA,mRNA, Non-Polyadenylated,mRNA, Polyadenylated,Non-Polyadenylated mRNA,Poly(A) RNA,Polyadenylated mRNA,Non Polyadenylated mRNA,Polyadenylated Messenger RNA,Polyadenylated RNA,RNA, Polyadenylated Messenger,mRNA, Non Polyadenylated
D014221 Triamcinolone A glucocorticoid given, as the free alcohol or in esterified form, orally, intramuscularly, by local injection, by inhalation, or applied topically in the management of various disorders in which corticosteroids are indicated. (From Martindale, The Extra Pharmacopoeia, 30th ed, p739) Aristocort,Volon
D015687 Cell Hypoxia A condition of decreased oxygen content at the cellular level. Anoxia, Cellular,Cell Anoxia,Hypoxia, Cellular,Anoxia, Cell,Anoxias, Cell,Anoxias, Cellular,Cell Anoxias,Cell Hypoxias,Cellular Anoxia,Cellular Anoxias,Cellular Hypoxia,Cellular Hypoxias,Hypoxia, Cell,Hypoxias, Cell,Hypoxias, Cellular
D015971 Gene Expression Regulation, Enzymologic Any of the processes by which nuclear, cytoplasmic, or intercellular factors influence the differential control of gene action in enzyme synthesis. Enzymologic Gene Expression Regulation,Regulation of Gene Expression, Enzymologic,Regulation, Gene Expression, Enzymologic
D017208 Rats, Wistar A strain of albino rat developed at the Wistar Institute that has spread widely at other institutions. This has markedly diluted the original strain. Wistar Rat,Rat, Wistar,Wistar Rats

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