title: Sustained p16INK4aexpression is required to prevent IR-induced tumorigenesis in mice.
abstract: Exposure of murine and human tissues to ionizing radiation (IR) induces the expression of p16INK4a, a tumor suppressor gene and senescence/aging biomarker. Increased p16INK4aexpression is often delayed several weeks post exposure to IR. In this context, it remains unclear if it occurs to suppress aberrant cellular growth of potentially transformed cells or is simply a result of IR-induced loss of tissue homeostasis. To address this question, we used a conditional p16INK4anull mouse model and determined the impact of p16INK4ainactivation long-term post exposure to IR. We found that, in vitro, bone marrow stromal cells exposed to IR enter DNA replication following p16INK4ainactivation. However, these cells did not resume growth; instead, they mostly underwent cell cycle arrest in G2. Similarly, delayed inactivation of p16INK4ain mice several weeks post exposure to IR resulted in increased BrdU incorporation and cancer incidence. In fact, we found that the onset of tumorigenesis was similar whether p16INK4awas inactivated before or after exposure to IR. Overall, our results suggest that IR-induced p16INK4adependent growth arrest is reversible in mice and that sustained p16INK4aexpression is necessary to protect against tumorigenesis.
authors: Centre de Recherche du Centre Hospitalier Universitaire Ste-Justine, Montréal, Canada.|Département de Pharmacologie, Université de Montréal, Montréal, Canada.
authors: L
authors: L
authors: Palacio
authors: Centre de Recherche du Centre Hospitalier Universitaire Ste-Justine, Montréal, Canada.|Département de Pharmacologie, Université de Montréal, Montréal, Canada.
authors: V
authors: V
authors: Krishnan
authors: Centre de Recherche du Centre Hospitalier Universitaire Ste-Justine, Montréal, Canada.
authors: N L O
authors: NL
authors: Le
authors: Departments of Medicine and Genetics, University of North Carolina School of Medicine, Chapel Hill, NC, USA.
authors: N E
authors: NE
authors: Sharpless
authors: Centre de Recherche du Centre Hospitalier Universitaire Ste-Justine, Montréal, Canada.|Département de Pharmacologie, Université de Montréal, Montréal, Canada.
authors: C M
authors: CM
authors: Beauséjour
mesh_terms: D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000378:metabolism / Q000473:pathology* / Q000528:radiation effects; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism*; D005260:Female; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009374:Neoplasms, Experimental / Q000378:metabolism / Q000473:pathology* / Q000532:radiotherapy; D011839:Radiation, Ionizing
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16