title: Cdkn1a deletion improves stem cell function and lifespan of mice with dysfunctional telomeres without accelerating cancer formation.
abstract: Telomere shortening limits the proliferative lifespan of human cells by activation of DNA damage pathways, including upregulation of the cell cycle inhibitor p21 (encoded by Cdkn1a, also known as Cip1 and Waf1)) (refs. 1-5). Telomere shortening in response to mutation of the gene encoding telomerase is associated with impaired organ maintenance and shortened lifespan in humans and in mice. The in vivo function of p21 in the context of telomere dysfunction is unknown. Here we show that deletion of p21 prolongs the lifespan of telomerase-deficient mice with dysfunctional telomeres. p21 deletion improved hematolymphopoiesis and the maintenance of intestinal epithelia without rescuing telomere function. Moreover, deletion of p21 rescued proliferation of intestinal progenitor cells and improved the repopulation capacity and self-renewal of hematopoietic stem cells from mice with dysfunctional telomeres. In these mice, apoptotic responses remained intact, and p21 deletion did not accelerate chromosomal instability or cancer formation. This study provides experimental evidence that telomere dysfunction induces p21-dependent checkpoints in vivo that can limit longevity at the organismal level.
authors.affiliation: Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany.
authors.forename: Aaheli Roy
authors.initials: AR
authors.lastname: Choudhury
authors.forename: Zhenyu
authors.initials: Z
authors.lastname: Ju
authors.forename: Meta W
authors.initials: MW
authors.lastname: Djojosubroto
authors.forename: Andrea
authors.initials: A
authors.lastname: Schienke
authors.forename: Andre
authors.initials: A
authors.lastname: Lechel
authors.forename: Sonja
authors.initials: S
authors.lastname: Schaetzlein
authors.forename: Hong
authors.initials: H
authors.lastname: Jiang
authors.forename: Anna
authors.initials: A
authors.lastname: Stepczynska
authors.forename: Chunfang
authors.initials: C
authors.lastname: Wang
authors.forename: Jan
authors.initials: J
authors.lastname: Buer
authors.forename: Han-Woong
authors.initials: HW
authors.lastname: Lee
authors.forename: Thomas
authors.initials: T
authors.lastname: von Zglinicki
authors.forename: Arnold
authors.initials: A
authors.lastname: Ganser
authors.forename: Peter
authors.initials: P
authors.lastname: Schirmacher
authors.forename: Hiromitsu
authors.initials: H
authors.lastname: Nakauchi
authors.forename: K Lenhard
authors.initials: KL
authors.lastname: Rudolph
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003433:Crosses, Genetic; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics*; D018450:Disease Progression; D017353:Gene Deletion; D007422:Intestines / Q000166:cytology; D008136:Longevity / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology; D013234:Stem Cells / Q000502:physiology*; D019098:Telomerase / Q000235:genetics; D016615:Telomere / Q000502:physiology*
chemical_list: C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D019098:Telomerase