Germline loss of PKM2 promotes metabolic distress and hepatocellular carcinoma
Name
Dayton-2016-Germline loss of PKM.pdf
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675.02 KB
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Adobe PDF
Checksum (MD5)
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Author(s)
Clish, Clary B.
Bronson, Roderick T.
Dayton, Talya L.
Gocheva, Vasilena
Miller, Kathryn
Israelsen, William James
Bhutkar, Arjun
Davidson, Shawn Michael
Luengo, Alba
Jacks, Tyler E.
Date Issued
May 2016
Journal
Genes & Development
Publisher
Cold Spring Harbor Laboratory Press
Citation
Dayton, Talya L. et al. “Germline Loss of PKM2 Promotes Metabolic Distress and Hepatocellular Carcinoma.” Genes & Development 30.9 (2016): 1020–1033.
Version
Final published version
Abstract
Alternative splicing of the Pkm gene product generates the PKM1 and PKM2 isoforms of pyruvate kinase (PK), and PKM2 expression is closely linked to embryogenesis, tissue regeneration, and cancer. To interrogate the functional requirement for PKM2 during development and tissue homeostasis, we generated germline PKM2-null mice (Pkm2[superscript −/−]). Unexpectedly, despite being the primary isoform expressed in most wild-type adult tissues, we found that Pkm2[superscript −/−] mice are viable and fertile. Thus, PKM2 is not required for embryonic or postnatal development. Loss of PKM2 leads to compensatory expression of PKM1 in the tissues that normally express PKM2. Strikingly, PKM2 loss leads to spontaneous development of hepatocellular carcinoma (HCC) with high penetrance that is accompanied by progressive changes in systemic metabolism characterized by altered systemic glucose homeostasis, inflammation, and hepatic steatosis. Therefore, in addition to its role in cancer metabolism, PKM2 plays a role in controlling systemic metabolic homeostasis and inflammation, thereby preventing HCC by a non-cell-autonomous mechanism.
MIT Department
Massachusetts Institute of Technology. Department of Biology
Koch Institute for Integrative Cancer Research at MIT
Terms of Use
Creative Commons Attribution-NonCommercial 4.0 International
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DOI of Published Version
https://doi.org/10.1101/gad.278549.116
