Dataset Information

Organ-specific PTB1-associated microRNAs determine expression of pyruvate kinase isoforms.

ABSTRACT: The Warburg effect is a well-known feature of cancer cells. However, its' functional significance hasn't been elucidated yet. Pyruvate kinase muscle (PKM), which is a rate-limiting glycolytic enzyme, has 2 isoforms, PKM1 and PKM2. It has been reported that PKM2 is a tumor-specific isoform and promotes the Warburg effect. Also, it has been thought that tumor cells switch their PKM isoform from PKM1 to PKM2 during tumor development. Here, we showed that this switching machinery was induced only in limited cases, based on PKM expression in normal tissues, and that brain-specific microRNA (miR)-124 and muscle-specific miR-133b regulated this machinery by controlling PKM expression through targeting polypyrimidine tract-binding protein 1 (PTB1), which is a splicer of the PKM gene. Also, we confirmed that the PKM2/PKM1 ratio was further elevated in other PKM2-dominant organs such as colon through the down-regulation of these PTB1-associated microRNAs during tumor development.

SUBMITTER: Taniguchi K

PROVIDER: S-EPMC4342556 | biostudies-other | 2015

REPOSITORIES: biostudies-other

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Organ-specific PTB1-associated microRNAs determine expression of pyruvate kinase isoforms.

Taniguchi Kohei K Ito Yuko Y Sugito Nobuhiko N Kumazaki Minami M Shinohara Haruka H Yamada Nami N Nakagawa Yoshihito Y Sugiyama Tarou T Futamura Manabu M Otsuki Yoshinori Y Yoshida Kazuhiro K Uchiyama Kazuhisa K Akao Yukihiro Y

Scientific reports 20150227

The Warburg effect is a well-known feature of cancer cells. However, its' functional significance hasn't been elucidated yet. Pyruvate kinase muscle (PKM), which is a rate-limiting glycolytic enzyme, has 2 isoforms, PKM1 and PKM2. It has been reported that PKM2 is a tumor-specific isoform and promotes the Warburg effect. Also, it has been thought that tumor cells switch their PKM isoform from PKM1 to PKM2 during tumor development. Here, we showed that this switching machinery was induced only in ...[more]

PMID: 25721733

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Project description:Phosphoinositides serve as address labels for recruiting peripheral cytoplasmic proteins to specific subcellular compartments, and as endogenous factors for modulating the activity of integral membrane proteins. Phosphatidylinositol 4,5-bisphosphate (PI(4,5)P(2)) is a plasma-membrane (PM)-specific phosphoinositide and a positive cofactor required for the activity of most PM channels and transporters. This requirement for phosphoinositide cofactors has been proposed to prevent PM channel/transporter activity during passage through the biosynthetic/secretory and endocytic pathways. To determine whether intracellularly localized channels are similarly "inactivated" at the PM, we studied PIP(2) modulation of intracellular TRPML1 channels. TRPML1 channels are primarily localized in lysosomes, but can also be detected temporarily in the PM upon lysosomal exocytosis. By directly patch-clamping isolated lysosomes, we previously found that lysosomal, but not PM-localized, TRPML1 is active with PI(3,5)P(2), a lysosome-specific PIP(2), as the underlying positive cofactor. Here we found that "silent" PM-localized TRPML1 could be activated by depleting PI(4,5)P(2) levels and/or by adding PI(3,5)P(2) to inside-out membrane patches. Unlike PM channels, surface-expressed TRPML1 underwent a unique and characteristic run-up upon patch excision, and was potently inhibited by a low micromolar concentration of PI(4,5)P(2). Conversely, depletion of PI(4,5)P(2) by either depolarization-induced activation or chemically induced translocation of 5'-phosphatase potentiated whole-cell TRPML1 currents. PI(3,5)P(2) activation and PI(4,5)P(2) inhibition of TRPML1 were mediated by distinct basic amino acid residues in a common PIP(2)-interacting domain. Thus, PI(4,5)P(2) may serve as a negative cofactor for intracellular channels such as TRPML1. Based on these results, we propose that phosphoinositide regulation sets compartment-specific activity codes for membrane channels and transporters.

Dataset Information

Organ-specific PTB1-associated microRNAs determine expression of pyruvate kinase isoforms.

Publications

Organ-specific PTB1-associated microRNAs determine expression of pyruvate kinase isoforms.

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