Smg1 haploinsufficiency predisposes to tumor formation and inflammation

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

Research output: Contribution to journalArticlepeer-review

44 Citations (Scopus)


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 theDNA 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 embryonic lethal, but Smg1 heterozygous mice showed a predisposition to a range of cancers, particularly lung and hematopoieticmalignancies, as well as development of chronic inflammation. These mice did not display deficiencies in known roles of SMG1, including nonsensemediated 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 haploinsufficiency 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
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number4
Publication statusPublished - 22 Jan 2013
Externally publishedYes


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