title: Smg1 haploinsufficiency predisposes to tumor formation and inflammation.
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.
authors.affiliation: Queensland Institute of Medical Research, Brisbane, QLD 4029, Australia. tara.roberts@qimr.edu.au
authors.forename: Tara L
authors.initials: TL
authors.lastname: Roberts
authors.forename: Uda
authors.initials: U
authors.lastname: Ho
authors.forename: John
authors.initials: J
authors.lastname: Luff
authors.forename: C Soon
authors.initials: CS
authors.lastname: Lee
authors.forename: Simon H
authors.initials: SH
authors.lastname: Apte
authors.forename: Kelli P A
authors.initials: KP
authors.lastname: MacDonald
authors.forename: Liza J
authors.initials: LJ
authors.lastname: Raggat
authors.forename: Allison R
authors.initials: AR
authors.lastname: Pettit
authors.forename: Carl A
authors.initials: CA
authors.lastname: Morrow
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Waters
authors.forename: Phil
authors.initials: P
authors.lastname: Chen
authors.forename: Rick G
authors.initials: RG
authors.lastname: Woods
authors.forename: Gethin P
authors.initials: GP
authors.lastname: Thomas
authors.forename: Liam
authors.initials: L
authors.lastname: St Pierre
authors.forename: Camile S
authors.initials: CS
authors.lastname: Farah
authors.forename: Raymond A
authors.initials: RA
authors.lastname: Clarke
authors.forename: James A L
authors.initials: JA
authors.lastname: Brown
authors.forename: Martin F
authors.initials: MF
authors.lastname: Lavin
mesh_terms: D000818:Animals; D001483:Base Sequence; D018076:DNA, Complementary / Q000235:genetics; D004195:Disease Models, Animal; D020022:Genetic Predisposition to Disease; D057895:Haploinsufficiency; D019337:Hematologic Neoplasms / Q000201:enzymology / Q000209:etiology / Q000235:genetics / Q000473:pathology; D006720:Homozygote; D007249:Inflammation / Q000150:complications / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D008175:Lung Neoplasms / Q000201:enzymology / Q000209:etiology / Q000235:genetics / Q000473:pathology; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009374:Neoplasms, Experimental / Q000201:enzymology / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency* / Q000235:genetics*
chemical_list: D018076:DNA, Complementary; D017346:Protein Serine-Threonine Kinases; C551743:Smg1 protein, mouse