The tumor suppressor Caliban regulates DNA damage-induced apoptosis through p53-dependent and -independent activity

We previously identified Caliban (Clbn) as the Drosophila homolog of human Serologically defined colon cancer antigen 1 gene and demonstrated that it could function as a tumor suppressor in

human non-small-cell lung cancer (NSCLC) cells, although its mode of action was unknown. Herein, we identify roles for Clbn in DNA damage response. We generate clbn knockout flies using

homologous recombination and demonstrate that they have a heightened sensitivity to irradiation. We show that normal Clbn function facilitates both p53-dependent and -independent DNA

damage-induced apoptosis. Clbn coordinates different apoptosis pathways, showing a two-stage upregulation following DNA damage. Clbn has proapoptotic functions, working with both caspase and

the proapoptotic gene Hid. Finally, ecotopic expression of clbn+ in NSCLC cells suppresses tumor formation in athymic nude mice. We conclude that Caliban is a regulator of DNA

damage-induced apoptosis, functioning as a tumor suppressor in both p53-dependent and -independent pathways.

We thank Drs Hermann Steller, Laura Johnston and Tin Tin Su; the Bloomington Stock Center for fly stocks; Dr Dong Han at National Center for Nanoscience and Technology for help with the

scanning electron microscope; and the members of the Bi laboratory for advice and discussions. We also thank Dr Mark Mortin for generating the knockout clbn flies and for critically reading

this manuscript. We are grateful for comments on this manuscript from Tehyen Chu and Brent McCright. This work was supported by grants from National Basic Research Program of China (973

Program grant no. 2010CB934004), National Natural Science Foundation of China (grant no. 30871388) and CAS Knowledge Innovation Program to XB and by the Food and Drug Administration, Center

for Biologics Evaluation and Research.

Y Wang and Z Wang: These authors contributed equally to this work.

CAS Key Laboratory for Biological Effects of Nanomaterials and Nanosafety, Institute of High Energy Physics, Chinese Academy of Sciences, Beijing, China

Cancer Center, Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China

Division of Cellular and Gene Therapies, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD, USA,

State Key Laboratory of Brain and Cognitive Sciences, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China

Department of Radiation Toxicology and Oncology, Beijing Institute of Radiation Medicine, Beijing, China

Supplementary Information accompanies the paper on the Oncogene website

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