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Protein kinase C? signaling regulates inhibitor of DNA binding 1 in the intestinal epithelium.

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

SUBMITTER: Hao F

PROVIDER: S-EPMC3093883 | biostudies-literature | 2011 May

REPOSITORIES: biostudies-literature

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

Hao Fang F Pysz Marybeth A MA Curry Kathryn J KJ Haas Kristin N KN Seedhouse Steven J SJ Black Adrian R AR Black Jennifer D JD

The Journal of biological chemistry 20110318 20

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 ...[more]

PMID: 21454537

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Project description:Protein kinase C alpha (PKCα) can activate both pro- and anti-tumorigenic signaling depending upon cellular context. Here, we investigated the role of PKCα in lung tumorigenesis in vivo. Gene expression data sets revealed that primary human non-small lung cancers (NSCLC) express significantly decreased PKCα levels, indicating that loss of PKCα expression is a recurrent event in NSCLC. We evaluated the functional relevance of PKCα loss during lung tumorigenesis in three murine lung adenocarcinoma models (LSL-Kras, LA2-Kras and urethane exposure). Genetic deletion of PKCα resulted in a significant increase in lung tumor number, size, burden and grade, bypass of oncogene-induced senescence, progression from adenoma to carcinoma and a significant decrease in survival in vivo. The tumor promoting effect of PKCα loss was reflected in enhanced Kras-mediated expansion of bronchio-alveolar stem cells (BASCs), putative tumor-initiating cells, both in vitro and in vivo. LSL-Kras/Prkca(-/-) mice exhibited a decrease in phospho-p38 MAPK in BASCs in vitro and in tumors in vivo, and treatment of LSL-Kras BASCs with a p38 inhibitor resulted in increased colony size indistinguishable from that observed in LSL-Kras/Prkca(-/-) BASCs. In addition, LSL-Kras/Prkca(-/-) BASCs exhibited a modest but reproducible increase in TGFβ1 mRNA, and addition of exogenous TGFβ1 to LSL-Kras BASCs results in enhanced growth similar to untreated BASCs from LSL-Kras/Prkca(-/-) mice. Conversely, a TGFβR1 inhibitor reversed the effects of PKCα loss in LSL-Kras/Prkca(-/-) BASCs. Finally, we identified the inhibitors of DNA binding (Id) Id1-3 and the Wilm's Tumor 1 as potential downstream targets of PKCα-dependent tumor suppressor activity in vitro and in vivo. We conclude that PKCα suppresses tumor initiation and progression, at least in part, through a PKCα-p38MAPK-TGFβ signaling axis that regulates tumor cell proliferation and Kras-induced senescence. Our results provide the first direct evidence that PKCα exhibits tumor suppressor activity in the lung in vivo.

Dataset Information

Protein kinase C? signaling regulates inhibitor of DNA binding 1 in the intestinal epithelium.

Publications

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

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