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Ablation of the Kinase NDR1 Predisposes Mice to the Development of T Cell Lymphoma

The kinase NDR1 functions as a haploinsufficient tumor suppressor by ensuring proper apoptotic responses. Lymphoma from Compromised Apoptosis The four members of the nuclear Dbf2–related (NDR) family of serine and threonine protein kinases act in a number of cellular processes, including proliferation, cytokinesis, and apoptosis. Two family members, LATS1 and LATS2, act as tumor suppressor proteins in flies and mice. Of the other two, NDR1 is abundant in organs of the immune system, whereas NDR2 is predominantly found in the gastrointestinal tract. Cornils et al. found that mouse lymphocytes deficient in NDR1 compensated for this loss by increasing the abundance of NDR2 protein in a posttranscriptional manner. Blockade of this compensatory mechanism resulted in increased resistance of cells to various extrinsic and intrinsic proapoptotic stimuli. Aged NDR1+/− and NDR1−/− mice were more susceptible to the development of T cell lymphoma than were their wild-type counterparts, and this was associated with a loss in total NDR protein. Correlating with this finding, the abundance of NDR proteins was less in samples of human T cell lymphomas than in normal T cells, suggesting that NDR1 acts as a tumor suppressor protein. 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.