Abstract
The expression of DCC (deleted in colorectal cancer) is often markedly reduced in colorectal and other cancers. However, the rarity of point mutations identified in DCC coding sequences and the lack of a tumor predisposition phenotype in DCC hemizygous mice have raised questions about its role as a tumor suppressor. DCC also mediates axon guidance and functions as a dependence receptor; such receptors create cellular states of dependence on their respective ligands by inducing apoptosis when unoccupied by ligand. We now show that DCC drives cell death independently of both the mitochondria-dependent pathway and the death receptor/caspase-8 pathway. Moreover, we demonstrate that DCC interacts with both caspase-3 and caspase-9 and drives the activation of caspase-3 through caspase-9 without a requirement for cytochrome c or Apaf-1. Hence, DCC defines an additional pathway for the apoptosome-independent caspase activation.
Highlights
Vogelstein and his colleagues [1] have shown that the development of colonic carcinoma from normal colonic epithelium is associated with the mutation of a specific set of genes
We demonstrate that DCC induces apoptosis in a caspase-9-dependent pathway, yet by a mechanism that is independent of the intrinsic apoptotic pathway
As DCC cleavage by caspases has been shown to be required for DCC proapoptotic activity [13], we first assessed whether caspase inhibition is sufficient to block DCC-induced cell death
Summary
Vogelstein and his colleagues [1] have shown that the development of colonic carcinoma from normal colonic epithelium is associated with the mutation of a specific set of genes. Allelic deletions (loss of heterozygosity) on chromosome 18q in more than 70% of primary colorectal tumors prompted the search for a tumor suppressor gene at that locus This search led to the cloning of a putative cell-surface receptor, DCC (deleted in colorectal cancer) [1]. We have shown that DCC is a dependence receptor [13] and functionally related to other dependence receptors such as p75NTR, the common neurotrophin receptor, the androgen receptor, and RET [14,15,16,17] Such receptors create cellular states of dependence on their respective ligands by inducing apoptosis when unoccupied by ligand but inhibiting apoptosis in the presence of ligand [13,14,15,16]. DCC defines an additional pathway for the apoptosome-independent caspase activation
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
