title: The cell cycle inhibitor p16(INK4A) sensitizes lymphoblastic leukemia cells to apoptosis by physiologic glucocorticoid levels.
abstract: The cyclin-dependent kinase inhibitor p16(INK4A) is frequently inactivated in childhood T-cell acute lymphoblastic leukemia. To investigate possible consequences of this genetic alteration for tumor development, we conditionally expressed p16(INK4A) in the T-cell acute lymphoblastic leukemia line CCRF-CEM, which carries a homozygous deletion of this gene. In agreement with its reported function, p16(INK4A) expression was associated with hypophosphorylation of the retinoblastoma protein pRB and stable cell cycle arrest in G(0)/G(1), documenting that the pRB/E2F pathway is functional in these cells. Unexpectedly, p16(INK4A) expression increased the sensitivity threshold for glucocorticoid (GC)-induced apoptosis from therapeutic to physiologic levels. As a possible explanation for this phenomenon, we found that p16(INK4A)-arrested cells had elevated GC receptor expression associated with enhanced GC-mediated transcriptional activity and increased responsiveness of the GC-regulated cyclin D3 gene. These data are supported by our previous findings that GC receptor levels critically influence GC sensitivity and imply that p16(INK4A) inactivation, in addition to allowing unrestricted proliferation, represents a mechanism by which lymphoid tumor cells might escape cell death triggered by endogenous GC.
authors.affiliation: Institute for General and Experimental Pathology, Division of Molecular Pathophysiology, University of Innsbruck Medical School and the Tyrolean Cancer Research Institute, A-6020 Innsbruck, Austria. Reinhard.Kofler@uibk.ac.at
authors.forename: M J
authors.initials: MJ
authors.lastname: Ausserlechner
authors.forename: P
authors.initials: P
authors.lastname: Obexer
authors.forename: G J
authors.initials: GJ
authors.lastname: Wiegers
authors.forename: B L
authors.initials: BL
authors.lastname: Hartmann
authors.forename: S
authors.initials: S
authors.lastname: Geley
authors.forename: R
authors.initials: R
authors.lastname: Kofler
mesh_terms: D017209:Apoptosis; D002453:Cell Cycle / Q000235:genetics / Q000502:physiology; D003001:Cloning, Molecular; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000502:physiology*; D017353:Gene Deletion; D005938:Glucocorticoids / Q000378:metabolism*; D006801:Humans; D007399:Interphase / Q000502:physiology; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics; D014407:Tumor Cells, Cultured
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; D005938:Glucocorticoids; D011965:Receptors, Glucocorticoid; D011994:Recombinant Proteins