Exon-centric regulation of pyruvate kinase M alternative splicing via mutually exclusive exons

Wang, Zhenxun; Chatterjee, Deblina; Jeon, Hyun Yong; Akerman, Martin; Heiden, Matthew G. Vander; Cantley, Lewis C.; Krainer, Adrian R.

doi:10.1093/jmcb/mjr030

Cited by 92 publications

(92 citation statements)

References 26 publications

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“…It is directly regulated at the transcriptional level by Wnt signaling (48), a pathway often upregulated in cancer (49). In turn, SRSF3 promotes several oncogenic AS events, such as exon 10 inclusion in the pyruvate kinase M gene, generating the PKM2 isoform, which promotes aerobic glycolysis in cancer cells (50). Our data therefore identify what we believe to be a novel mechanism underlying SRSF3 oncogenic function, namely the regulation of MDM4 AS and, in turn, the suppression of p53 activity.…”

Section: Discussionmentioning

confidence: 99%

Antisense oligonucleotide–mediated MDM4 exon 6 skipping impairs tumor growth

Dewaele

Tabaglio

Willekens

et al. 2015

Journal of Clinical Investigation

142

178

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Section: Discussionmentioning

confidence: 99%

Antisense oligonucleotide–mediated MDM4 exon 6 skipping impairs tumor growth

Dewaele

Tabaglio

Willekens

et al. 2015

Journal of Clinical Investigation

142

178

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“…HIF-1 activates the expression of pyruvate kinase M2 (PKM2), which encodes pyruvate kinase isoforms PKM1 and PKM2 by alternative splicing that includes sequences encoded by exon 9 or exon 10, respectively, which differ at 23 of 56 amino acids. In cancer cells, the expression of splicing factors favors the generation of PKM2 mRNA (62)(63)(64)(65). PKM2 promotes tumor growth (66) by a complex and growing list of activities.…”

Section: Figurementioning

confidence: 99%

HIF-1 mediates metabolic responses to intratumoral hypoxia and oncogenic mutations

Semenza¹

2013

J. Clin. Invest.

1,084

999

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Hypoxia occurs frequently in human cancers and induces adaptive changes in cell metabolism that include a switch from oxidative phosphorylation to glycolysis, increased glycogen synthesis, and a switch from glucose to glutamine as the major substrate for fatty acid synthesis. This broad metabolic reprogramming is coordinated at the transcriptional level by HIF-1, which functions as a master regulator to balance oxygen supply and demand. HIF-1 is also activated in cancer cells by tumor suppressor (e.g., VHL) loss of function and oncogene gain of function (leading to PI3K/AKT/mTOR activity) and mediates metabolic alterations that drive cancer progression and resistance to therapy. Inhibitors of HIF-1 or metabolic enzymes may impair the metabolic flexibility of cancer cells and make them more sensitive to anticancer drugs. IntroductionAll human cells require a constant supply of O 2 to carry out oxidative phosphorylation in the mitochondria for ATP generation. Under hypoxic conditions when O 2 availability is reduced, cells generally respond in three ways: (a) cell proliferation is inhibited to prevent any further increase in the number of O 2 -consuming cells; (b) the rate of oxidative phosphorylation is decreased and the rate of glycolysis is increased in order to decrease O 2 consumption per cell; and (c) the production of angiogenic factors is increased in order to increase O 2 delivery. Mutations in cancer cells dysregulate cell growth and metabolism, but the mechanisms and consequences of this dysregulation vary widely from one cancer to another and even one from cancer cell to another. In some cancer cells, O 2 still regulates the rate of cell proliferation, whereas others continue to divide even under severely hypoxic conditions; some cancers are well vascularized and perfused, whereas most cancers contain steep O 2 gradients that reflect the distance to the nearest blood vessel, the number of intervening cells and their metabolic activity, and the rate at which blood is flowing through the vessel. The metabolism of individual cancer cells reflects the presence of particular genetic alterations, which may alter metabolism in an O 2 -independent manner, as well as the spatial and temporal heterogeneity of O 2 availability within the tumor microenvironment. This Review summarizes the role of HIF-1 in the regulation of cancer cell metabolism, focusing primarily on the use of glucose as a metabolic substrate.

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“…We next investigated the molecular mechanisms underlying the PKM2 increase in DM1 tissues. In cancer, upregulation of splicing factors, such as PTB, hnRNPA1/A2, and SRSF3 (23)(24)(25), induces PKM2 expression. We were unable to detect a correlation between these proteins and PKM2 upregulation in DM1 skeletal muscle, however, albeit with the caveat that subtle changes might not have been detected owing to low protein levels (Fig.…”

Section: Pkm2 Levels Are Regulated By Celf1 and Minimally By Mbnl1 Andmentioning

confidence: 99%

Reexpression of pyruvate kinase M2 in type 1 myofibers correlates with altered glucose metabolism in myotonic dystrophy

Gao

Cooper

2013

Proc. Natl. Acad. Sci. U.S.A.

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Myotonic dystrophy type 1 (DM1) is caused by expansion of CTG repeats in the 3′ UTR of the DMPK gene. Expression of CUG expansion (CUG exp ) RNA produces a toxic gain of function by disrupting the functions of RNA splicing factors, such as MBNL1 and CELF1, leading to splicing changes associated with clinical abnormalities. Progressive skeletal muscle weakness and wasting is one of the most prominent clinical features in DM1; however, the underlying mechanisms remain unclear. Here we report that the embryonic M2 isoform of pyruvate kinase (PKM2), a key enzyme contributing to the Warburg effect in cancer, is significantly induced in DM1 tissue and mouse models owing to aberrant splicing. Expression of PKM2 in DM1 skeletal muscle is restricted to the type 1 fibers, which are particularly susceptible to wasting in DM1. Using antisense oligonucleotides to shift PKM splicing toward increased PKM2 expression, we observed increased glucose consumption with reduced oxidative metabolism in cell culture and increased respiratory exchange ratio in mice, suggesting defects in energy metabolism conferred by PKM2 expression. We propose that PKM2 expression induces changes in type 1 fibers associated with muscle atrophy and muscle weakness in DM1. muscular dystrophy | redirected splicing | striated muscle development | alternative splicing M yotonic dystrophy (DM) is the most common adult-onset form of muscular dystrophy (1, 2). It is caused by expanded CTG repeats in the 3′ UTR of the DMPK gene (type 1; DM1) or expanded CCTG repeats in the first intron of the CNBP gene (type 2; DM2) (3-5). The RNAs transcribed from the expanded CTG or CCTG alleles produce a dominant toxic gain of function (2, 6). The toxicity of CUG-and CCUG-expanded RNAs (CUG exp and CCUG exp RNA) involves two main pathogenic mechanisms. First, CUG exp or CCUG exp RNAs bind and sequester muscleblindlike (MBNL) proteins within ribonuclear foci, resulting in MBNL loss of function (7,8). Second, CUG exp RNA activates protein kinase C, which phosphorylates and stabilizes CELF1, resulting in its elevation and gain of function (9). MBNL and CELF1 proteins regulate alternative splicing during development, and disruption of their functions leads to aberrant splicing transitions implicated in such manifestations of DM as myotonia and insulin resistance (2).Progressive muscle weakness and wasting are among the most prominent clinical features of DM1 (1). In contrast to other forms of muscular dystrophy, such as Duchenne muscular dystrophy, the muscle weakness and wasting in DM1 is not accompanied by overt regeneration, fibrosis and necrosis. Instead, the most prominent histological abnormalities in DM1 are centralized nuclei and slow myofiber (type 1 fiber) atrophy (1). Early studies suggested that reduced protein synthesis and an imbalance of anabolism and catabolism may be responsible for the muscle wasting in DM1 (10, 11). Recent studies have shown that abnormal T-tubule biogenesis and calcium signaling, along with increased glycogen synthase kinase 3β (GSK3β) ...

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Exon-centric regulation of pyruvate kinase M alternative splicing via mutually exclusive exons

Cited by 92 publications

References 26 publications

Antisense oligonucleotide–mediated MDM4 exon 6 skipping impairs tumor growth

Antisense oligonucleotide–mediated MDM4 exon 6 skipping impairs tumor growth

HIF-1 mediates metabolic responses to intratumoral hypoxia and oncogenic mutations

Reexpression of pyruvate kinase M2 in type 1 myofibers correlates with altered glucose metabolism in myotonic dystrophy

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