Protein kinase Cα signaling regulates inhibitor of DNA binding 1 in the intestinal epithelium

Fang Hao, Marybeth A. Pysz, Kathryn J. Curry, Kristin N. Haas, Steven J. Seedhouse, Adrian R. Black, Jennifer D. Black

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

Increasing evidence supports a role for PKCα 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 PKCα 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 PKCα and Id1 was supported by the demonstration that (a) down-regulation of Id1 at the crypt/villus junction coincides with PKCα activation, and (b) loss of PKCα in intestinal tumors is associated with increased levels of nuclear Id1. Manipulation of PKCα activity in IEC-18 nontransformed intestinal crypt cells determined that PKCα suppresses Id1 mRNA and protein via an Erk-dependent mechanism. PKCα, but not PKCδ, 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 PKCα. Notably, Id1 expression was elevated in the intestinal epithelium of PKCα-knock-out mice, confirming that PKCα regulates Id1 in vivo. A wider role for PKCα in control of inhibitor of DNA binding factors is supported by its ability to downregulate 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 PKCα → Erk ⊣ Id1 → cyclin D1 signaling axis in the maintenance of intestinal homeostasis.

Original languageEnglish (US)
Pages (from-to)18104-18117
Number of pages14
JournalJournal of Biological Chemistry
Volume286
Issue number20
DOIs
StatePublished - May 20 2011

Fingerprint

Intestinal Mucosa
Protein Kinase C
Tumors
Cyclin D1
DNA
Cells
Colonic Neoplasms
Nuclear Proteins
Down-Regulation
Isoenzymes
Demonstrations
Neoplasms
Chemical activation
Tissue
Messenger RNA
Knockout Mice
Antibodies
Homeostasis
Maintenance
Proteins

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Protein kinase Cα signaling regulates inhibitor of DNA binding 1 in the intestinal epithelium. / Hao, Fang; Pysz, Marybeth A.; Curry, Kathryn J.; Haas, Kristin N.; Seedhouse, Steven J.; Black, Adrian R.; Black, Jennifer D.

In: Journal of Biological Chemistry, Vol. 286, No. 20, 20.05.2011, p. 18104-18117.

Research output: Contribution to journalArticle

Hao, Fang ; Pysz, Marybeth A. ; Curry, Kathryn J. ; Haas, Kristin N. ; Seedhouse, Steven J. ; Black, Adrian R. ; Black, Jennifer D. / Protein kinase Cα signaling regulates inhibitor of DNA binding 1 in the intestinal epithelium. In: Journal of Biological Chemistry. 2011 ; Vol. 286, No. 20. pp. 18104-18117.
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