| First Author | Hao F | Year | 2011 |
| Journal | J Biol Chem | Volume | 286 |
| Issue | 20 | Pages | 18104-17 |
| PubMed ID | 21454537 | Mgi Jnum | J:172682 |
| Mgi Id | MGI:5008530 | Doi | 10.1074/jbc.M110.208488 |
| Citation | Hao F, et al. (2011) Protein Kinase C{alpha} Signaling Regulates Inhibitor of DNA Binding 1 in the Intestinal Epithelium. J Biol Chem 286(20):18104-17 |
| abstractText | Increasing evidence supports a role for PKCalpha in growth arrest and tumor suppression in the intestinal epithelium. In contrast, the Id1 transcriptional repressor has pro-proliferative and tumorigenic properties in this tissue. Here, we identify Id1 as a novel target of PKCalpha signaling. Using a highly specific antibody and a combined morphological/biochemical approach, we establish that Id1 is a nuclear protein restricted to proliferating intestinal crypt cells. A relationship between PKCalpha and Id1 was supported by the demonstration that (a) down-regulation of Id1 at the crypt/villus junction coincides with PKCalpha activation, and (b) loss of PKCalpha in intestinal tumors is associated with increased levels of nuclear Id1. Manipulation of PKCalpha activity in IEC-18 nontransformed intestinal crypt cells determined that PKCalpha suppresses Id1 mRNA and protein via an Erk-dependent mechanism. PKCalpha, but not PKCdelta, also inhibited Id1 expression in colon cancer cells. Id1 was found to regulate cyclin D1 levels in IEC-18 and colon cancer cells, pointing to a role for Id1 suppression in the antiproliferative/tumor suppressive activities of PKCalpha. Notably, Id1 expression was elevated in the intestinal epithelium of PKCalpha-knock-out mice, confirming that PKCalpha regulates Id1 in vivo. A wider role for PKCalpha in control of inhibitor of DNA binding factors is supported by its ability to down-regulate Id2 and Id3 in IEC-18 cells, although their suppression is more modest than that of Id1. This study provides the first demonstrated link between a specific PKC isozyme and inhibitor of DNA binding factors, and it points to a role for a PKCalpha --> Erk dash, vertical Id1 --> cyclin D1 signaling axis in the maintenance of intestinal homeostasis. |
