Smg1 haploinsufficiency predisposes to tumor formation and inflammation

Tara L Roberts, Uda Ho, John Luff, C Soon Lee, Simon H Apte, Kelli PA MacDonald, Liza J Raggat, Allison R Pettit, Carl A Morrow, Michael J Waters, Phil Chen, Rick G Woods, Gethin Thomas, Liam St. Pierre, Camile S Farah, Raymond A Clarke, James A. L. Brown, Martin F Lavin

    Research output: Contribution to journalArticle

    25 Citations (Scopus)

    Abstract

    SMG1 is a member of the phosphoinositide kinase-like kinase family of proteins that includes ATM, ATR, and DNA-PK, proteins with known roles in DNA damage and cellular stress responses. SMG1 has a well-characterized role in nonsense-mediated decay as well as suggested roles in the DNA damage response, resistance to oxidative stress, regulation of hypoxic responses, and apoptosis. To understand the roles of SMG1 further, we generated a Genetrap Smg1 mouse model. Smg1 homozygous KO mice were early embryoniclethal, but Smg1 heterozygous mice showed a predisposition to a range of cancers, particularly lung and hematopoietic malignancies,as well as development of chronic inflammation. These mice did not display deficiencies in known roles of SMG1, including nonsense mediated decay. However, they showed elevated basal tissue and serum cytokine levels, indicating low-level inflammation before the development of tumors. Smg1 heterozygous mice also showed evidence of oxidative damage in tissues. These data suggest that the inflammation observed in Smg1 haploin sufficiency contributes to susceptibility to cancer and that Smg1-deficient animals represent a model of inflammation-enhanced cancer development.
    Original languageEnglish
    Pages (from-to)E285-E294
    Number of pages10
    JournalProceedings of the National Academy of Sciences of the United States of America
    Volume110
    Issue number4
    Early online dateDec 2012
    DOIs
    Publication statusPublished - Jan 2013

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