PKCα tumor suppression in the intestine is associated with transcriptional and translational inhibition of cyclin D1

Marybeth A. Pysz, Olga V. Leontieva, Nicholas W. Bateman, Joshua M. Uronis, Kathryn J. Curry, David W. Threadgill, Klaus Peter Janssen, Sylvie Robine, Anna Velcich, Leonard H. Augenlicht, Adrian R. Black, Jennifer D. Black

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Abstract

Alterations in PKC isozyme expression and aberrant induction of cyclin D1 are early events in intestinal tumorigenesis. Previous studies have identified cyclin D1 as a major target in the antiproliferative effects of PKCα in non-transformed intestinal cells; however, a link between PKC signaling and cyclin D1 in colon cancer remained to be established. The current study further characterized PKC isozyme expression in intestinal neoplasms and explored the consequences of restoring PKCα or PKCδ in a panel of colon carcinoma cell lines. Consistent with patterns of PKC expression in primary tumors, PKCα and δ levels were generally reduced in colon carcinoma cell lines, PKCβII was elevated and PKCe{open} showed variable expression, thus establishing the suitability of these models for analysis of PKC signaling. While colon cancer cells were insensitive to the effects of PKC agonists on cyclin D1 levels, restoration of PKCα downregulated cyclin D1 by two independent mechanisms. PKCα expression consistently (a) reduced steady-state levels of cyclin D1 by a novel transcriptional mechanism not previously seen in non-transformed cells, and (b) re-established the ability of PKC agonists to activate the translational repressor 4E-BP1 and inhibit cyclin D1 translation. In contrast, PKCδ had modest and variable effects on cyclin D1 steady-state levels and failed to restore responsiveness to PKC agonists. Notably, PKCα expression blocked anchorage-independent growth in colon cancer cells via a mechanism partially dependent on cyclin D1 deficiency, while PKCδ had only minor effects. Loss of PKCα and effects of its re-expression were independent of the status of the APC/β-catenin signaling pathway or known genetic alterations, indicating that they are a general characteristic of colon tumors. Thus, PKCα is a potent negative regulator of cyclin D1 expression and anchorage-independent cell growth in colon tumor cells, findings that offer important perspectives on the frequent loss of this isozyme during intestinal carcinogenesis.

Original languageEnglish (US)
Pages (from-to)1415-1428
Number of pages14
JournalExperimental Cell Research
Volume315
Issue number8
DOIs
StatePublished - May 1 2009

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Keywords

  • 4E-BP1
  • Colon cancer
  • Cyclin D1
  • Mouse models
  • Protein kinase C
  • Transcriptional control
  • β-catenin

ASJC Scopus subject areas

  • Cell Biology

Cite this

Pysz, M. A., Leontieva, O. V., Bateman, N. W., Uronis, J. M., Curry, K. J., Threadgill, D. W., Janssen, K. P., Robine, S., Velcich, A., Augenlicht, L. H., Black, A. R., & Black, J. D. (2009). PKCα tumor suppression in the intestine is associated with transcriptional and translational inhibition of cyclin D1. Experimental Cell Research, 315(8), 1415-1428. https://doi.org/10.1016/j.yexcr.2009.02.002