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.
Laboratory of Apoptosis and Cancer Biology, Howard Hughes Medical Institute, The Rockefeller University, New York, New York 10065, USA.
María
M
García-Fernández
Holger
H
Kissel
Samara
S
Brown
Travis
T
Gorenc
Andrew J
AJ
Schile
Shahin
S
Rafii
Sarit
S
Larisch
Hermann
H
Steller
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