Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0009402 (colorectal cancer)
 53,228 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The guidance of developing axons in the nervous system is mediated partly by diffusible chemoattractants secreted by axonal target cells. Netrins are chemoattractants for commissural axons in the vertebrate spinal cord, but the mechanisms through which they produce their effects are unknown. We show that Deleted in Colorectal Cancer (DCC), a transmembrane protein of the immunoglobulin superfamily, is expressed on spinal commissural axons and possesses netrin-1-binding activity. Moreover, an antibody to DCC selectively blocks the netrin-1-dependent outgrowth of commissural axons in vitro. These results indicate that DCC is a receptor or a component of a receptor that mediates the effects of netrin-1 on commissural axons, and they complement genetic evidence for interactions between DCC and netrin homologs in C. elegans and Drosophila.
 ...
PMID:Deleted in Colorectal Cancer (DCC) encodes a netrin receptor. 886 2

UNC-6 netrin, a laminin-related protein secreted from neuroglia and neurons along the ventral midline, orients migrating cells and pioneering growth cones on the nematode epidermis. UNC-5, a cell surface protein expressed on motile cells and pioneer axons, orients movements away from UNC-6 sources. UNC-40, a homolog of the cell surface proteins DCC (Deleted in Colorectal Cancer) and neogenin, is also expressed on motile cells and pioneer neurons. UNC-40 acts cell autonomously to orient movement toward UNC-6 sources. For cells coexpressing UNC-5, it helps orient movement away from UNC-6 sources. Finally, UNC-40 helps determine the dorsoventral position of cells undergoing purely longitudinal migrations. Together with the recent report that DCC is a netrin receptor in vertebrates, our results suggest that UNC-40 is a component of UNC-6 receptors on motile cells.
 ...
PMID:UNC-40, a C. elegans homolog of DCC (Deleted in Colorectal Cancer), is required in motile cells responding to UNC-6 netrin cues. 886 3

The DCC (Deleted in colorectal cancer) gene was first identified as a candidate for a tumour-suppressor gene on human chromosome 18q. More recently, in vitro studies in rodents have provided evidence that DCC might function as a receptor for the axonal chemoattractant netrin-1. Inactivation of the murine Dcc gene caused defects in axonal projections that are similar to those observed in netrin-1-deficient mice but did not affect growth, differentiation, morphogenesis or tumorigenesis in mouse intestine. These observations fail to support a tumour-suppressor function for Dcc, but are consistent with the hypothesis that DCC is a component of a receptor for netrin-1.
 ...
PMID:Phenotype of mice lacking functional Deleted in colorectal cancer (Dcc) gene. 912 37

The netrins are laminin-like axon guidance molecules that are conserved among Caenorhabditis elegans, Drosophila, and vertebrates and that have chemoattractive and chemorepellant properties. To study the possible actions of this gene family in the developing and adult mammalian nervous systems, we have cloned a partial cDNA which corresponds to a region conserved among chick netrin-1, netrin-2, and unc-6 and studied its expression and that of a netrin receptor, dcc, the deleted in colorectal cancer gene, in the developing and adult rat CNS. The localization of cells expressing netrin or dcc suggests that these genes, in addition to their actions in defining the ventral midline, may act in controlling retinal ganglion cell axon guidance in the optic nerve, cell migration in the developing cerebellum and olfactory epithelium, and development and maintenance of connections to the substantia nigra and corpus striatum.
 ...
PMID:Netrin and netrin receptor expression in the embryonic mammalian nervous system suggests roles in retinal, striatal, nigral, and cerebellar development. 914 59

Embryonic retinal ganglion cell (RGC) axons must extend toward and grow through the optic disc to exit the eye into the optic nerve. In the embryonic mouse eye, we found that immunoreactivity for the axon guidance molecule netrin-1 was specifically on neuroepithelial cells at the disk surrounding exiting RGC axons, and RGC axons express the netrin receptor, DCC (deleted in colorectal cancer). In vitro, anti-DCC antibodies reduced RGC neurite outgrowth responses to netrin-1. In netrin-1- and DCC-deficient embryos, RGC axon pathfinding to the disc was unaffected; however, axons failed to exit into the optic nerve, resulting in optic nerve hypoplasia. Thus, netrin-1 through DCC appears to guide RGC axons locally at the optic disc rather than at long range, apparently reflecting the localization of netrin-1 protein to the vicinity of netrin-1-producing cells at the optic disc.
 ...
PMID:Netrin-1 and DCC mediate axon guidance locally at the optic disc: loss of function leads to optic nerve hypoplasia. 933 50

DCC (deleted in colorectal cancer) is postulated to function as transmembrane receptor for the axon and cell guidance factor netrin-1. We report here that the DCC cytoplasmic domain binds to proteins encoded by mammalian homologs of the Drosophila seven in absentia (sina) gene, as well as Drosophila Sina. Sina has a critical role in R7 photoreceptor development and shows upward of 85% amino acid identity with its mammalian homologs (termed Siahs), but the function of the Sina/Siah proteins has not been defined. We sought, therefore, to characterize further their interaction with DCC. Immunofluorescence studies suggested the Sina/Siah proteins localized predominantly in the cytoplasm and in association with DCC. DCC was found to be ubiquitinated and the Sina/Siah proteins regulated its expression. Proteasome inhibitors blocked the effects of Sina/Siah on DCC, and the Sina/Siah proteins interacted with ubiquitin-conjugating enzymes (Ubcs). A mutant Siah protein lacking the amino-terminal Ubc-binding sequences complexed with DCC, but did not degrade it. The in vivo interaction between Sina/Siah and DCC was confirmed through studies of transgenic Drosophila lines in which DCC and Sina were ectopically expressed in the eye. Taken together, the data imply that the Sina/Siah proteins regulate DCC and perhaps other proteins via the ubiquitin-proteasome pathway.
 ...
PMID:Mammalian homologs of seven in absentia regulate DCC via the ubiquitin-proteasome pathway. 933 32

Netrin-1 promotes outgrowth of axons in vitro through the receptor Deleted in Colorectal Cancer (DCC) and elicits turning of axons within embryonic explants when presented as a point source. It is not known whether netrin-1 alone can elicit turning nor whether DCC mediates the turning response. We show that Xenopus retinal ganglion cell growth cones orient rapidly toward a pipette ejecting netrin-1, an effect blocked by antibodies to DCC. In vitro, netrin-1 induces a complex growth cone morphology reminiscent of that at the optic nerve head, a site of netrin-1 expression in vivo. These results demonstrate that netrin-1 can function alone to induce turning, implicate DCC in this response, and support the idea that netrin-1 contributes to steering axons out of the retina.
 ...
PMID:Turning of retinal growth cones in a netrin-1 gradient mediated by the netrin receptor DCC. 942 45

Netrin-1 is known to function as a chemoattractant for several classes of developing axons and as a chemorepellent for other classes of axons, apparently dependent on the receptor type expressed by responsive cells. In culture, growth cones of embryonic Xenopus spinal neurons exhibited chemoattractive turning toward the source of netrin-1 but showed chemorepulsive responses in the presence of a competitive analog of cAMP or an inhibitor of protein kinase A. Both attractive and repulsive responses were abolished by depleting extracellular calcium and by adding a blocking antibody against the netrin-1 receptor Deleted in Colorectal Cancer. Thus, nerve growth cones may respond to the same guidance cue with opposite turning behavior, dependent on other coincident signals that set the level of cytosolic cAMP.
 ...
PMID:cAMP-dependent growth cone guidance by netrin-1. 942 46

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.
 ...
PMID:The DCC gene product induces apoptosis by a mechanism requiring receptor proteolysis. 979 14

Netrins, a family of laminin-related secreted proteins, have critical roles in axon guidance and cell migration during development. The deleted in colorectal cancer (DCC) protein has been implicated as a netrin-1 receptor component. The expression and function of netrins in adult tissues remain unknown, and direct interaction of netrin-1 with DCC has not been demonstrated. We cloned the human netrin-1 (NTN1L) gene, mapped it to chromosome 17p12-13, and found that it encodes a 604 amino acid protein with 98% identity to mouse netrin-1 and 50% identity with the Caenorhabditis elegans UNC-6 protein. NTN1L transcripts were detected in essentially all normal adult tissues studied, and markedly reduced or absent NTN1L expression was seen in approximately 50% of brain tumors and neuroblastomas. In one neuroblastoma, missense mutations at highly conserved NTN1L codons were found. Netrin-1 protein could be cross-linked to DCC protein on the cell surface, but it did not immunoprecipitate with DCC in the absence of cross-linking and it failed to bind to a soluble fusion protein containing the entire DCC extracellular domain. Our findings demonstrating NTN1L loss of expression and mutations suggest that NTN1L alterations may contribute to the development of some cancers. Furthermore, the binding of netrin-1 to DCC appears to depend on the presence of a coreceptor or accessory proteins.
 ...
PMID:Netrin-1: interaction with deleted in colorectal cancer (DCC) and alterations in brain tumors and neuroblastomas. 995 Feb 16


1 2 3 4 5 6 7 8 9 10 Next >>