TY - JOUR
T1 - Smg1 haploinsufficiency predisposes to tumor formation and inflammation
AU - Roberts, Tara L.
AU - Ho, Uda
AU - Luff, John
AU - Lee, C. Soon
AU - Apte, Simon H.
AU - MacDonald, Kelli P.A.
AU - Raggat, Liza J.
AU - Pettit, Allison R.
AU - Morrow, Carl A.
AU - Waters, Michael J.
AU - Chen, Phil
AU - Woods, Rick G.
AU - Thomas, Gethin P.
AU - Pierre, Liam St
AU - Farah, Camile S.
AU - Clarke, Raymond A.
AU - Brown, James A.L.
AU - Lavin, Martin F.
PY - 2013/1/22
Y1 - 2013/1/22
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84872842115&partnerID=8YFLogxK
U2 - 10.1073/pnas.1215696110
DO - 10.1073/pnas.1215696110
M3 - Article
C2 - 23277562
AN - SCOPUS:84872842115
SN - 0027-8424
VL - 110
SP - E285-E294
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 4
ER -
