Hypoxic regulation of the 6‐phosphofructo‐2‐kinase/fructose‐2,6‐bisphosphatase gene family (PFKFB‐1–4) expression in vivo

FEBS Letters

Minchenko, Oleksandr¹  Caro, Jaime²  Opentanova, Iryna¹ 

[1] Department of Molecular Biology, Institute of Biochemistry, National Academy of Science of Ukraine, Kyiv 01601, Ukraine;Cardeza Foundation for Hematologic Research, Department of Medicine, Jefferson Medical College of Thomas Jefferson University, Curtis Bldg. 810, 1015 Walnut Street, Philadelphia, PA 19107, USA

关键词: Fructose-2;    6-bisphosphate;    Phosphofructokinase-2;    Hypoxia;    Hypoxia-inducible factor;    Glycolysis;    F-2;    6-BP;    fructose-2;    6-bisphosphate;    PFK-1;    phosphofructokinase-1;    PFKFB or PFK-2;    6-phosphofructo-2-kinase/fructose-2;    6-bisphosphatase;    HIF;    hypoxia-inducible factor;    Glut-1;    glucose transporter-1;   

DOI  :  10.1016/S0014-5793(03)01179-7

学科分类：生物化学/生物物理

来源: John Wiley & Sons Ltd.

【 摘 要 】

When oxygen becomes limiting, cells shift primarily to a glycolytic mode for generation of energy. A key regulator of glycolytic flux is fructose-2,6-bisphosphate (F-2,6-BP), a potent allosteric regulator of 6-phosphofructo-1-kinase (PFK-1). The levels of F-2,6-BP are maintained by a family of bifunctional enzymes, 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFKFB or PFK-2), which have both kinase and phosphatase activities. Each member of the enzyme family is characterized by their phosphatase:kinase activity ratio (K:B) and their tissue-specific expression. Previous work demonstrated that one of the PFK-2 isozyme genes, PFKFB-3, was induced by hypoxia through the hypoxia-inducible factor-1 (HIF-1) pathway. In this study we examined the basal and hypoxic expression of three members of this family in different organs of mice. Our findings indicate that all four isozymes (PFKFB-1–4) are responsive to hypoxia in vivo. However, their basal level of expression and hypoxia responsiveness varies in the different organs studied. Particularly, PFKFB-1 is highly expressed in liver, heart and skeletal muscle, with the highest response to hypoxia found in the testis. PFKFB-2 is mainly expressed in the lungs, brain and heart. However, the highest hypoxia responses are found only in liver and testis. PFKFB-3 has a variable low basal level of expression in all organs, except skeletal muscle, where it is highly expressed. Most importantly, its hypoxia responsiveness is the most ample of all three genes, being strongly induced in the lungs, liver, kidney, brain, heart and testis. Further studies showed that PFKFB-1 and PFKFB-2 were highly responsive to hypoxia mimics such as transition metals, iron chelators and inhibitors of HIF hydroxylases, suggesting that the hypoxia responsiveness of these genes is also regulated by HIF proteins. In summary, our data demonstrate that PFK-2 genes are responsive to hypoxia in vivo, indicating a physiological role in the adaptation of the organism to environmental or localized hypoxia/ischemia.

【 授权许可】

Unknown