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An inducible gene product for 6-phosphofructo-2-kinase with an AU-rich instability element: role in tumor cell glycolysis and the Warburg effect.

ABSTRACT: Cancer cells maintain a high glycolytic rate even in the presence of oxygen, a phenomenon first described over 70 years ago and known historically as the Warburg effect. Fructose 2,6-bisphosphate is a powerful allosteric regulator of glycolysis that acts to stimulate the activity of 6-phosphofructo-1-kinase (PFK-1), the most important control point in mammalian glycolysis. The steady state concentration of fructose 2,6-bisphosphate in turn depends on the activity of the enzyme 6-phosphofructo-2-kinase (PFK-2)/fructose-2, 6-bisphosphatase, which is expressed in several tissue-specific isoforms. We report herein the identification of a gene product for this enzyme that is induced by proinflammatory stimuli and which is distinguished by the presence of multiple copies of the AUUUA mRNA instability motif in its 3'-untranslated end. This inducible gene for PFK-2 is expressed constitutively in several human cancer cell lines and was found to be required for tumor cell growth in vitro and in vivo. Inhibition of inducible PFK-2 protein expression decreased the intracellular level of 5-phosphoribosyl-1-pyrophosphate, a product of the pentose phosphate pathway and an important precursor for nucleic acid biosynthesis. These studies identify a regulatory isoenzyme that may be essential for tumor growth and provide an explanation for long-standing observations concerning the apparent coupling of enhanced glycolysis and cell proliferation.

SUBMITTER: Chesney J

PROVIDER: S-EPMC15892 | biostudies-literature | 1999 Mar

REPOSITORIES: biostudies-literature

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An inducible gene product for 6-phosphofructo-2-kinase with an AU-rich instability element: role in tumor cell glycolysis and the Warburg effect.

Chesney J J Mitchell R R Benigni F F Bacher M M Spiegel L L Al-Abed Y Y Han J H JH Metz C C Bucala R R

Proceedings of the National Academy of Sciences of the United States of America 19990301 6

Cancer cells maintain a high glycolytic rate even in the presence of oxygen, a phenomenon first described over 70 years ago and known historically as the Warburg effect. Fructose 2,6-bisphosphate is a powerful allosteric regulator of glycolysis that acts to stimulate the activity of 6-phosphofructo-1-kinase (PFK-1), the most important control point in mammalian glycolysis. The steady state concentration of fructose 2,6-bisphosphate in turn depends on the activity of the enzyme 6-phosphofructo-2- ...[more]

PMID: 10077634

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Project description:Fru-2,6-P2 (fructose 2,6-bisphosphate) is a signal molecule that controls glycolysis. Since its discovery more than 20 years ago, inroads have been made towards the understanding of the structure-function relationships in PFK-2 (6-phosphofructo-2-kinase)/FBPase-2 (fructose-2,6-bisphosphatase), the homodimeric bifunctional enzyme that catalyses the synthesis and degradation of Fru-2,6-P2. The FBPase-2 domain of the enzyme subunit bears sequence, mechanistic and structural similarity to the histidine phosphatase family of enzymes. The PFK-2 domain was originally thought to resemble bacterial PFK-1 (6-phosphofructo-1-kinase), but this proved not to be correct. Molecular modelling of the PFK-2 domain revealed that, instead, it has the same fold as adenylate kinase. This was confirmed by X-ray crystallography. A PFK-2/FBPase-2 sequence in the genome of one prokaryote, the proteobacterium Desulfovibrio desulfuricans, could be the result of horizontal gene transfer from a eukaryote distantly related to all other organisms, possibly a protist. This, together with the presence of PFK-2/FBPase-2 genes in trypanosomatids (albeit with possibly only one of the domains active), indicates that fusion of genes initially coding for separate PFK-2 and FBPase-2 domains might have occurred early in evolution. In the enzyme homodimer, the PFK-2 domains come together in a head-to-head like fashion, whereas the FBPase-2 domains can function as monomers. There are four PFK-2/FBPase-2 isoenzymes in mammals, each coded by a different gene that expresses several isoforms of each isoenzyme. In these genes, regulatory sequences have been identified which account for their long-term control by hormones and tissue-specific transcription factors. One of these, HNF-6 (hepatocyte nuclear factor-6), was discovered in this way. As to short-term control, the liver isoenzyme is phosphorylated at the N-terminus, adjacent to the PFK-2 domain, by PKA (cAMP-dependent protein kinase), leading to PFK-2 inactivation and FBPase-2 activation. In contrast, the heart isoenzyme is phosphorylated at the C-terminus by several protein kinases in different signalling pathways, resulting in PFK-2 activation.

Project description:The yeast M-NM-6-crystallin Zta1p interacts specifically with RNA sequences rich in adenine and uracil (AU-rich element). We have looked for possible targets of Zta1p through a comparative transcriptional analysis of the yeast defective in ZTA1 (M-NM-^Tzta1) versus the wild-type by microarray. This revealed that a group of genes implicated on amino acid biosynthesis are affected by the lack of ZTA1. The effect on one of the targets ARG4 was studied in more detail, revealing a clear positive correlation between ZTA1 and ARG4 expression at the mRNA level. We demonstrate that Zta1p is able to bind specifically to the 3M-bM-^@M-^YUTR AU-rich elements of ARG4 mRNA in vitro, suggesting that the mechanism by which ZTA1 modulates the expression of ARG4 is probably mediated by this mRNA binding ability. Moreover, the expression of ZTA1 is also under the control of the TOR pathway, and under Gcn4p, which regulates genes implicated in the response to nutrient availability and the general amino acid control (GAAC). In summary, our results shed light on the functional role of the M-NM-6-crystallin family as stress response proteins, with a conserved functional role, from yeast to humans, in the post-transcriptional regulation of genes that need to be rapidly activated for cell defense. Triplicate biological replicate experiments were performed, where the two strains, M-bM-^HM-^Fzta1 and wild-type, were grown in the presence or absence of hydrogen peroxide. The experimental design was defined to directly compare the M-bM-^HM-^Fzta1 versus the wild-type strain in either of the two hydrogen peroxide treatment conditions (i.e. treated M-bM-^HM-^Fzta1 versus treated wt, or untreated M-bM-^HM-^Fzta1 versus untreated wt). A duplicate hybridization on a separate array with dye swapping was performed in each case to correct for dye bias effects. Thus, a total of 12 array data sets were produced as a result of processing three experimental pairs of samples, for each of two treatment conditions, with dye swap duplicates.

Dataset Information

An inducible gene product for 6-phosphofructo-2-kinase with an AU-rich instability element: role in tumor cell glycolysis and the Warburg effect.

Publications

An inducible gene product for 6-phosphofructo-2-kinase with an AU-rich instability element: role in tumor cell glycolysis and the Warburg effect.

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