Sept4/ARTS is required for stem cell apoptosis and tumor suppression.
Inhibitor of Apoptosis Proteins (IAPs) are frequently overexpressed in tumors and have become promising targets for developing anti-cancer drugs. IAPs can be inhibited by natural antagonists, but a physiological requirement of mammalian IAP antagonists remains to be established. Here we show that deletion of the mouse Sept4 gene, which encodes the IAP antagonist ARTS, promotes tumor development. Sept4-null mice have increased numbers of hematopoietic stem and progenitor cells, elevated XIAP protein, increased resistance to cell death, and accelerated tumor development in an Eμ-Myc background. These phenotypes are partially suppressed by inactivation of XIAP. Our results suggest that apoptosis plays an important role as a frontline defense against cancer by restricting the number of normal stem cells.
García-Fernández
María
M
Laboratory of Apoptosis and Cancer Biology, Howard Hughes Medical Institute, The Rockefeller University, New York, New York 10065, USA.
Kissel
Holger
H
Brown
Samara
S
Gorenc
Travis
T
Schile
Andrew J
AJ
Rafii
Shahin
S
Larisch
Sarit
S
Steller
Hermann
H
D000818:Animals; D017209:Apoptosis; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism; D002452:Cell Count; D002478:Cells, Cultured; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005434:Flow Cytometry; D019204:GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D019337:Hematologic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D053208:Kaplan-Meier Estimate; D008221:Lymphoid Tissue / Q000378:metabolism / Q000473:pathology; D008223:Lymphoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D058112:Septins; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism*; D013489:Suppression, Genetic; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000235:genetics / Q000378:metabolism
D003598:Cytoskeletal Proteins; D051636:X-Linked Inhibitor of Apoptosis Protein; D019204:GTP-Binding Proteins; C115474:Sept4 protein, mouse; D058112:Septins