Smg1 haploinsufficiency predisposes to tumor formation and inflammation

Roberts, Tara L., Ho, Uda, Luff, John, Lee, C. Soon, Apte, Simon H., MacDonald, Kelli P. A., Raggatt, Liza-Jane, Pettit, Allison R., Morrow, Carl A., Waters, Michael J., Chen, Phil, Woods, Rick G., Thomas, Gethin P., St. Pierre, Liam, Farah, Camile S., Clarke, Raymond A., Brown, James A. L. and Lavin, Martin F. (2013) Smg1 haploinsufficiency predisposes to tumor formation and inflammation. PNAS: Proceedings of the National Academy of Sciences of the United States of America, 110 4: E285-E294. doi:10.1073/pnas.1215696110


Author Roberts, Tara L.
Ho, Uda
Luff, John
Lee, C. Soon
Apte, Simon H.
MacDonald, Kelli P. A.
Raggatt, Liza-Jane
Pettit, Allison R.
Morrow, Carl A.
Waters, Michael J.
Chen, Phil
Woods, Rick G.
Thomas, Gethin P.
St. Pierre, Liam
Farah, Camile S.
Clarke, Raymond A.
Brown, James A. L.
Lavin, Martin F.
Title Smg1 haploinsufficiency predisposes to tumor formation and inflammation
Journal name PNAS: Proceedings of the National Academy of Sciences of the United States of America   Check publisher's open access policy
ISSN 0027-8424
1091-6490
Publication date 2013-01-22
Year available 2012
Sub-type Article (original research)
DOI 10.1073/pnas.1215696110
Open Access Status Not Open Access
Volume 110
Issue 4
Start page E285
End page E294
Total pages 10
Place of publication Washington, DC, United States
Publisher National Academy of Sciences
Collection year 2013
Language eng
Formatted 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 embryonic lethal, 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 haploinsufficiency contributes to susceptibility to cancer and that Smg1-deficient animals represent a model of inflammation-enhanced cancer development.
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ
Additional Notes Published online before print December 31, 2012

 
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Created: Thu, 17 Jan 2013, 14:06:16 EST by Susan Allen on behalf of Institute for Molecular Bioscience