title: Ablation of the kinase NDR1 predisposes mice to the development of T cell lymphoma.
abstract: Defective apoptosis contributes to the development of various human malignancies. The kinases nuclear Dbf2-related 1 (NDR1) and NDR2 mediate apoptosis downstream of the tumor suppressor proteins RASSF1A (Ras association domain family member 1A) and MST1 (mammalian Ste20-like kinase 1). To further analyze the role of NDR1 in apoptosis, we generated NDR1-deficient mice. Although NDR1 is activated by both intrinsic and extrinsic proapoptotic stimuli, which indicates a role for NDR1 in regulating apoptosis, NDR1-deficient T cells underwent apoptosis in a manner similar to that of wild-type cells in response to different proapoptotic stimuli. Analysis of the abundances of NDR1 and NDR2 proteins revealed that loss of NDR1 was functionally compensated for by an increase in the abundance of NDR2 protein. Despite this compensation, NDR1(-/-) and NDR1(+/-) mice were more prone to the development of T cell lymphomas than were wild-type mice. Tumor development in mice and humans was accompanied by a decrease in the overall amounts of NDR proteins in T cell lymphoma samples. Thus, reduction in the abundance of NDR1 triggered a decrease in the total amount of both isoforms. Together, our data suggest that a reduction in the abundances of the NDR proteins results in defective responses to proapoptotic stimuli, thereby facilitating the development of tumors.
authors.affiliation: Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, CH-4058 Basel, Switzerland. hauke.cornils@fmi.ch
authors.forename: Hauke
authors.initials: H
authors.lastname: Cornils
authors.forename: Mario R
authors.initials: MR
authors.lastname: Stegert
authors.forename: Alexander
authors.initials: A
authors.lastname: Hergovich
authors.forename: Debby
authors.initials: D
authors.lastname: Hynx
authors.forename: Debora
authors.initials: D
authors.lastname: Schmitz
authors.forename: Stephan
authors.initials: S
authors.lastname: Dirnhofer
authors.forename: Brian A
authors.initials: BA
authors.lastname: Hemmings
mesh_terms: D000818:Animals; D017209:Apoptosis; D006801:Humans; D016399:Lymphoma, T-Cell / Q000209:etiology*; D051379:Mice; D018345:Mice, Knockout; D017346:Protein Serine-Threonine Kinases / Q000032:analysis / Q000172:deficiency / Q000502:physiology*
chemical_list: C552947:NDR1 protein kinase, mouse; C552948:NDR2 protein kinase, mouse; D017346:Protein Serine-Threonine Kinases