The alternative splicing repressors hnRNP A1/A2 and PTB influence pyruvate kinase isoform expression and cell metabolism.
Cynthia V. Clower,Deblina Chatterjee,Zhenxun Wang,Lewis C. Cantley,Matthew G. Vander Heiden,Adrian R. Krainer +5 more
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TLDR
It is shown that the M1-specific exon is actively repressed in cancer-cell lines—although some M1 mRNA is expressed in cell lines derived from brain tumors—and that the related splicing repressors hnRNP A1 and A2, as well as the polypyrimidine-tract-binding protein PTB contribute to this control.Abstract:
Cancer cells preferentially metabolize glucose by aerobic glycolysis, characterized by increased lactate production. This distinctive metabolism involves expression of the embryonic M2 isozyme of pyruvate kinase, in contrast to the M1 isozyme normally expressed in differentiated cells, and it confers a proliferative advantage to tumor cells. The M1 and M2 pyruvate-kinase isozymes are expressed from a single gene through alternative splicing of a pair of mutually exclusive exons. We measured the expression of M1 and M2 mRNA and protein isoforms in mouse tissues, tumor cell lines, and during terminal differentiation of muscle cells, and show that alternative splicing regulation is sufficient to account for the levels of expressed protein isoforms. We further show that the M1-specific exon is actively repressed in cancer-cell lines—although some M1 mRNA is expressed in cell lines derived from brain tumors—and demonstrate that the related splicing repressors hnRNP A1 and A2, as well as the polypyrimidine-tract-binding protein PTB, contribute to this control. Downregulation of these splicing repressors in cancer-cell lines using shRNAs rescues M1 isoform expression and decreases the extent of lactate production. These findings extend the links between alternative splicing and cancer, and begin to define some of the factors responsible for the switch to aerobic glycolysis.read more
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HIF-1 mediates metabolic responses to intratumoral hypoxia and oncogenic mutations
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Mechanisms and Regulation of Alternative Pre-mRNA Splicing
Yeon J. Lee,Donald C. Rio +1 more
TL;DR: These studies provide mechanistic insights into how spliceosome assembly, dynamics, and catalysis occur; how alternative splicing is regulated and evolves; and how splicing can be disrupted by cis- and trans-acting mutations leading to disease states.
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Breast-cancer-secreted miR-122 reprograms glucose metabolism in premetastatic niche to promote metastasis
Miranda Y. Fong,Weiying Zhou,Liang Liu,Aileen Y. Alontaga,Manasa Chandra,Jonathan Ashby,Amy Y. M. Chow,Sean Timothy Francis O’Connor,Shasha Li,Andrew R. Chin,George Somlo,Melanie R. Palomares,Zhuo Li,Jacob R. Tremblay,Akihiro Tsuyada,Guoqiang Sun,Michael A. Reid,Xiwei Wu,Piotr Swiderski,Xiubao Ren,Yanhong Shi,Mei Kong,Wenwan Zhong,Yuan Chen,Shizhen Emily Wang +24 more
TL;DR: It is demonstrated that, by modifying glucose utilization by recipient premetastatic niche cells, cancer-derived extracellular miR-122 is able to reprogram systemic energy metabolism to facilitate disease progression.
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Alternative pre-mRNA splicing regulation in cancer: pathways and programs unhinged
Charles J. David,James L. Manley +1 more
TL;DR: Emerging insights into this process indicate that pathways that are frequently deregulated in cancer often play important roles in promoting aberrant splicing, which in turn contributes to all aspects of tumor biology.
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Pyruvate kinase M2 activators promote tetramer formation and suppress tumorigenesis.
Dimitrios Anastasiou,Yimin Yu,William J. Israelsen,Jian-kang Jiang,Matthew B. Boxer,Bum Soo Hong,Wolfram Tempel,Svetoslav Dimov,Min Shen,Abhishek K. Jha,Hua Yang,Katherine R. Mattaini,Christian M. Metallo,Brian P. Fiske,Kevin D. Courtney,Scott E. Malstrom,Tahsin M. Khan,Charles Kung,Amanda P. Skoumbourdis,Henrike Veith,Noel Southall,Martin J. Walsh,Kyle R. Brimacombe,William Leister,Sophia Y. Lunt,Zachary R. Johnson,Katharine E. Yen,Kaiko Kunii,Shawn M. Davidson,Heather R. Christofk,Christopher P. Austin,James Inglese,Marian H. Harris,John M. Asara,Gregory Stephanopoulos,Francesco G. Salituro,Shengfang Jin,Lenny Dang,Douglas S. Auld,Hee-Won Park,Lewis C. Cantley,Craig J. Thomas,Matthew G. Vander Heiden,Matthew G. Vander Heiden +43 more
TL;DR: It is shown that expression of PKM1, the pyruvate kinase isoform with high constitutive activity, or exposure to published small molecule PKM2 activators inhibit growth of xenograft tumors and support the notion that small molecule activation ofPKM2 can interfere with anabolic metabolism.
References
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Journal ArticleDOI
Mechanisms of Alternative Pre-Messenger RNA Splicing
TL;DR: This review describes what is currently known of the molecular mechanisms that control changes in splice site choice and starts with the best-characterized systems from the Drosophila sex determination pathway, and then describes the regulators of other systems about whose mechanisms there is some data.
Journal ArticleDOI
The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth
Heather R. Christofk,Matthew G. Vander Heiden,Marian H. Harris,Arvind Ramanathan,Robert E. Gerszten,Robert E. Gerszten,Ru Wei,Mark D. Fleming,Stuart L. Schreiber,Stuart L. Schreiber,Lewis C. Cantley,Lewis C. Cantley +11 more
TL;DR: It is demonstrated that M2 expression is necessary for aerobic glycolysis and that this metabolic phenotype provides a selective growth advantage for tumour cells in vivo.
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HnRNP proteins controlled by c-Myc deregulate pyruvate kinase mRNA splicing in cancer
TL;DR: A pathway that regulates an alternative splicing event required for tumour cell proliferation is defined, establishing a relevance to cancer, and it is demonstrated that human gliomas overexpress c-Myc, PTB, hnRNPA1 and hn RNPA2 in a manner that correlates with PKM2 expression.
Journal ArticleDOI
Pyruvate kinase M2 is a phosphotyrosine-binding protein
Heather R. Christofk,Matthew G. Vander Heiden,Ning Wu,John M. Asara,John M. Asara,Lewis C. Cantley +5 more
TL;DR: The results indicate that expression of this phosphotyrosine-binding form of pyruvate kinase is critical for rapid growth in cancer cells and Diverts glucose metabolites from energy production to anabolic processes when cells are stimulated by certain growth factors.
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The gene encoding the splicing factor SF2/ASF is a proto-oncogene
TL;DR: It is found that the splicing factor SF2/ASF is upregulated in various human tumors, in part due to amplification of its gene, SFRS1, and can act as an oncoprotein and is a potential target for cancer therapy.