Mediation of the DCC apoptotic signal by DIP13 alpha.
DCC (deleted in colorectal cancer) is a candidate tumor suppressor gene. However the function of DCC remains elusive. Previously, we demonstrated that forced expression of DCC induces apoptosis or cell cycle arrest (Chen, Y. Q., Hsieh, J. T., Yao, F., Fang, B., Pong, R. C., Cipriano, S. C. & Krepulat, F. (1999) Oncogene 18, 2747-2754). To delineate the DCC-induced apoptotic pathway, we have identified a protein, DIP13 alpha, which interacts with DCC. The DIP13 alpha protein has a pleckstrin homology domain and a phosphotyrosine binding domain. It interacts with a region on the DCC cytoplasmic domain that is required for the induction of apoptosis. Although ectopic expression of DIP13 alpha alone causes only a slight increase in apoptosis, co-expression of DCC and DIP13 alpha results in an approximately 5-fold increase in apoptosis. Removal of the DCC-interacting domain on DIP13 alpha abolishes its ability to enhance DCC-induced apoptosis. Inhibition of endogenous DIP13 alpha expression by small interfering RNA blocks DCC-induced apoptosis. Our data suggest that DIP13 alpha is a mediator of the DCC apoptotic pathway.
Liu
Jiayou
J
Department of Pathology, Wayne State University, Detroit, Michigan 48201, USA.
Yao
Fayi
F
Wu
Ruping
R
Morgan
Michael
M
Thorburn
Andrew
A
Finley
Russell L
RL
Chen
Yong Q
YQ
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D017209:Apoptosis; D002352:Carrier Proteins / Q000737:chemistry / Q000378:metabolism*; D015179:Colorectal Neoplasms / Q000235:genetics; D016163:Genes, DCC; D008969:Molecular Sequence Data; D010449:Peptide Mapping; D019000:Phosphotyrosine / Q000378:metabolism; D034741:RNA, Small Interfering; D022661:RNA, Untranslated / Q000378:metabolism; D011817:Rabbits; D014407:Tumor Cells, Cultured; D015003:Yeasts
C464801:APPL1 protein, human; D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D034741:RNA, Small Interfering; D022661:RNA, Untranslated; D019000:Phosphotyrosine