The DCC gene product induces apoptosis by a mechanism requiring receptor proteolysis.
The development of colonic carcinoma is associated with the mutation of a specific set of genes. One of these, DCC (deleted in colorectal cancer), is a candidate tumour-suppressor gene, and encodes a receptor for netrin-1, a molecule involved in axon guidance. Loss of DCC expression in tumours is not restricted to colon carcinoma, and, although there is no increase in the frequency of tumour formation in DCC hemizygous mice, reestablishment of DCC expression suppresses tumorigenicity. However, the mechanism of action of DCC is unknown. Here we show that DCC induces apoptosis in the absence of ligand binding, but blocks apoptosis when engaged by netrin-1. Furthermore, DCC is a caspase substrate, and mutation of the site at which caspase-3 cleaves DCC suppresses the pro-apoptotic effect of DCC completely. These results indicate that DCC may function as a tumour-suppressor protein by inducing apoptosis in settings in which ligand is unavailable (for example, during metastasis or tumour growth beyond local blood supply) through functional caspase cascades by a mechanism that requires cleavage of DCC at Asp 1,290.
Mehlen
P
P
Program on Aging, The Burnham Institute, La Jolla, California 92037, USA.
Rabizadeh
S
S
Snipas
S J
SJ
Assa-Munt
N
N
Salvesen
G S
GS
Bredesen
D E
DE
D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D001224:Aspartic Acid / Q000378:metabolism; D018938:Caco-2 Cells; D053179:Caspase 7; D020169:Caspases / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000235:genetics* / Q000502:physiology; D002460:Cell Line; D000075389:DCC Receptor; D016163:Genes, DCC; D016147:Genes, Tumor Suppressor; D006801:Humans; D051379:Mice; D016297:Mutagenesis, Site-Directed; D009414:Nerve Growth Factors / Q000378:metabolism; D000075388:Netrin-1; D011956:Receptors, Cell Surface / Q000235:genetics / Q000502:physiology; D014162:Transfection; D025521:Tumor Suppressor Proteins
D015815:Cell Adhesion Molecules; D000075389:DCC Receptor; C501909:DCC protein, human; C501910:Dcc protein, mouse; C000617351:NTN1 protein, human; D009414:Nerve Growth Factors; C000617353:Ntn1 protein, mouse; D011956:Receptors, Cell Surface; D025521:Tumor Suppressor Proteins; D000075388:Netrin-1; D001224:Aspartic Acid; C505520:CASP7 protein, human; C505524:Casp7 protein, mouse; D053179:Caspase 7; D020169:Caspases