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Gene Review

Pklr  -  pyruvate kinase, liver and RBC

Rattus norvegicus

Synonyms: L-PK, PK1, PKL, Pklg, Pyruvate kinase PKLR, ...
 
 
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Disease relevance of Pklr

 

High impact information on Pklr

  • The position of this kinase in the cascade is as follows, where the arrows denote phosphorylation: [Formula: see text] The phosphorylation by PKF, like phosphorylation by the other kinases, is at a tyrosine residue and causes the substrate kinase (PKL) to become active [6].
  • In contrast, if it occurred, the decrease in L-PK activity by the nonpromoting agents amobarbital (CAS: 57-43-2) and diphenylhydantoin [7].
  • In contrast to L-PK activity, the activity of K-type pyruvate kinase (K-PK) was induced by injections of the carcinogen diethylnitrosamine (CAS: 55-18-5) or the hepatotoxin CCl4 (CAS: 56-23-5) or by the feeding of 3'-MeDAB [7].
  • Here we report the purification and identification of a transcription factor that recognizes the carbohydrate response element (ChRE) within the promoter of the L-type pyruvate kinase (LPK) gene [8].
  • However, merely the ability to bind MLTF/USF does not seem to be sufficient to confer a GlRE activity: those elements in which one E box has been destroyed and the other has been transformed into a consensus MLTF/USF sequence bind MLTF/USF efficiently but do not confer a high glucose responsiveness on the L-PK gene promoter [9].
 

Biological context of Pklr

  • Reporter gene assay showed that these two factors synergistically activated the L-PK promoter containing the 5'-flanking region up to -189 [10].
  • The total sequence of a 13,021 base-pair (bp) genomic fragment containing the rat L-type pyruvate kinase (L-PK) gene was determined by "shot gun" sequencing [11].
  • Various types of repetitive sequences exist in the L-PK gene, especially two ID (identifier) sequences located in the second intron and the 11th exon [11].
  • Like the chicken PK-M1 gene, the rat L-PK gene exhibits a fully conserved exon-intron structure, with 11 exons and 10 introns [11].
  • We demonstrate here the cross-talk between oxygen and glucose in the regulation of L-type pyruvate kinase (L-PK) gene expression in the liver [1].
 

Anatomical context of Pklr

  • In primary rat hepatocyte cultures the expression of the L-PK gene on mRNA and on protein level was induced by venous pO(2), whereas its glucose-dependent induction occurred predominantly under arterial pO(2) [1].
  • Nevertheless, the L-PK gene is re-expressed at a very low level in cultured 266.6 cells derived from an exocrine pancreas carcinoma [12].
  • The L-PK gene is early activated in endodermal tissues, e.g. yolk sac and primitive intestine; it remains transcribed in fetal pancreas [12].
  • In fibroblasts, the overexpression of HNF4 transactivates the L-PK promoter [9].
  • In acidophilic cell components with less pronounced glycogen storage L-PK expression was similar to that of pseudolobules showing a slightly reduced content of this enzyme protein [13].
 

Associations of Pklr with chemical compounds

  • A comparison of the 5'-flanking region of the L-PK gene with the same regions of liver-specific or non-specific, cyclic-AMP-responsive or non-responsive genes was also made [11].
  • To investigate which DNA elements are involved in hepatocyte-specific expression of the L-type isozyme, we performed transient DNA transfer experiments with PKL/chloramphenicol acetyltransferase fusion genes [14].
  • Overexpressed ChREBP, but not MLX, relieved the WY14643 inhibition of L-PK [15].
  • In primary culture of rat hepatocytes, 0.2 mM fructose in the presence of 20 or 40 mM glucose stimulated the activity of the L-PK gene promoter fused with the chloramphenicol acetyltransferase reporter gene, regardless of the addition of insulin, through the glucose/insulin response element [16].
  • Sequences from -4300 to +12 of the L-PK gene directed an increase in CAT activity when hepatocytes were switched from media containing 10 mM lactate to 25 mM glucose [17].
 

Other interactions of Pklr

  • In rat INS-1E beta cells, only Pklr expression was suppressed by low glucose as in islets, while Insr and Insrr were suppressed by high and increased by low glucose levels [18].
  • The proximal 5'-flanking sequence of the L-PK gene therefore appears to function in vitro as an efficient liver-specific promoter which requires the binding of the liver factor HNF1 and which is also stimulated by the binding of another liver-specific factor, LF-A1 [19].
 

Analytical, diagnostic and therapeutic context of Pklr

  • The L-PK mRNA level in rat liver changed after partial hepatectomy, during development and on intake of a high carbohydrate diet, while the level of LF-B1 mRNA remained unchanged or altered reciprocally [2].
  • Hepatic expression of the genes encoding L-type pyruvate kinase (L-PK) and S14 is induced in rats upon feeding them a high carbohydrate, low fat diet [20].
  • Microinjection of antibodies against the ubiquitous transcription factor USF2 inhibited L-PK promoter activity in beta- and INS-1 cells incubated at 30 mM glucose by 71-87% [3].
  • These data suggest that L-PK was activated by a dephosphorylation mechanism during rat liver perfusion [21].
  • The extent of phosphorylation of L-PK was also estimated by incubation of the liver extract with [gamma-32P]ATP, protein kinase, and cyclic AMP, and measurement of 32Pi incorporated in L-PK by specific immunoprecipitation [21].

References

  1. Cross-talk between the signals hypoxia and glucose at the glucose response element of the L-type pyruvate kinase gene. Krones, A., Jungermann, K., Kietzmann, T. Endocrinology (2001) [Pubmed]
  2. Alteration in L-type pyruvate kinase gene expression is not associated with the LF-B1 mRNA level. Imai, E., Noguchi, T., Takenaka, M., Yamada, K., Matsuda, T., Monaci, P., Nicosia, A., Tanaka, T. Biochem. Biophys. Res. Commun. (1991) [Pubmed]
  3. Upstream stimulatory factor-2 (USF2) activity is required for glucose stimulation of L-pyruvate kinase promoter activity in single living islet beta-cells. Kennedy, H.J., Viollet, B., Rafiq, I., Kahn, A., Rutter, G.A. J. Biol. Chem. (1997) [Pubmed]
  4. Pyruvate kinase isoenzymes in altered foci and carcinoma of rat liver. Reinacher, M., Eigenbrodt, E., Gerbracht, U., Zenk, G., Timmermann-Trosiener, I., Bentley, P., Waechter, F., Schulte-Hermann, R. Carcinogenesis (1986) [Pubmed]
  5. Cytoimmunochemical study of pyruvate kinase isoenzymes in rat liver. Gali, P., Hartmann, L. Liver (1982) [Pubmed]
  6. A mouse homolog to the avian sarcoma virus src protein is a member of a protein kinase cascade. Spector, M., Pepinsky, R.B., Vogt, V.M., Racker, E. Cell (1981) [Pubmed]
  7. Decrease in L-type pyruvate kinase activity in rat liver by some promoters of hepatocarcinogenesis. Yanagi, S., Sakamoto, M., Ninomiya, Y., Kamiya, T. J. Natl. Cancer Inst. (1984) [Pubmed]
  8. A glucose-responsive transcription factor that regulates carbohydrate metabolism in the liver. Yamashita, H., Takenoshita, M., Sakurai, M., Bruick, R.K., Henzel, W.J., Shillinglaw, W., Arnot, D., Uyeda, K. Proc. Natl. Acad. Sci. U.S.A. (2001) [Pubmed]
  9. Functional characterization of the L-type pyruvate kinase gene glucose response complex. Diaz Guerra, M.J., Bergot, M.O., Martinez, A., Cuif, M.H., Kahn, A., Raymondjean, M. Mol. Cell. Biol. (1993) [Pubmed]
  10. Nuclear factor 1 family members interact with hepatocyte nuclear factor 1alpha to synergistically activate L-type pyruvate kinase gene transcription. Satoh, S., Noaki, T., Ishigure, T., Osada, S., Imagawa, M., Miura, N., Yamada, K., Noguchi, T. J. Biol. Chem. (2005) [Pubmed]
  11. Structure of the rat L-type pyruvate kinase gene. Cognet, M., Lone, Y.C., Vaulont, S., Kahn, A., Marie, J. J. Mol. Biol. (1987) [Pubmed]
  12. Expression of the L-type pyruvate kinase gene and the hepatocyte nuclear factor 4 transcription factor in exocrine and endocrine pancreas. Miquerol, L., Lopez, S., Cartier, N., Tulliez, M., Raymondjean, M., Kahn, A. J. Biol. Chem. (1994) [Pubmed]
  13. Pyruvate kinase isoenzyme shift from L-type to M2-type is a late event in hepatocarcinogenesis induced in rats by a choline-deficient/DL-ethionine-supplemented diet. Hacker, H.J., Steinberg, P., Bannasch, P. Carcinogenesis (1998) [Pubmed]
  14. Identification and characterization of hepatocyte-specific regulatory regions of the rat pyruvate kinase L gene. The synergistic effect of multiple elements. Yamada, K., Noguchi, T., Matsuda, T., Takenaka, M., Monaci, P., Nicosia, A., Tanaka, T. J. Biol. Chem. (1990) [Pubmed]
  15. Regulation of rat hepatic L-pyruvate kinase promoter composition and activity by glucose, n-3 polyunsaturated fatty acids, and peroxisome proliferator-activated receptor-alpha agonist. Xu, J., Christian, B., Jump, D.B. J. Biol. Chem. (2006) [Pubmed]
  16. Respective roles of glucose, fructose, and insulin in the regulation of the liver-specific pyruvate kinase gene promoter. Doiron, B., Cuif, M.H., Kahn, A., Diaz-Guerra, M.J. J. Biol. Chem. (1994) [Pubmed]
  17. Localization of the carbohydrate response element of the rat L-type pyruvate kinase gene. Thompson, K.S., Towle, H.C. J. Biol. Chem. (1991) [Pubmed]
  18. Glucose concentration and AMP-dependent kinase activation regulate expression of insulin receptor family members in rat islets and INS-1E beta cells. Raile, K., Klammt, J., Laue, S., Garten, A., Blüher, M., Kralisch, S., Klöting, N., Kiess, W. Diabetologia (2005) [Pubmed]
  19. Analysis by cell-free transcription of the liver-specific pyruvate kinase gene promoter. Vaulont, S., Puzenat, N., Kahn, A., Raymondjean, M. Mol. Cell. Biol. (1989) [Pubmed]
  20. Carbohydrate regulation of hepatic gene expression. Evidence against a role for the upstream stimulatory factor. Kaytor, E.N., Shih, H., Towle, H.C. J. Biol. Chem. (1997) [Pubmed]
  21. Dephosphorylation of L-pyruvate kinase during rat liver hepatocyte isolation. Riou, J.P., Audigier, C., Laville, M., Beylot, M., Pigeon, P., Mornex, R. Arch. Biochem. Biophys. (1985) [Pubmed]
 
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