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J. Biol. Chem., Vol. 280, Issue 31, 28412-28423, August 5, 2005

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Protein Kinase C II Plays an Essential Role in Dendritic Cell Differentiation and Autoregulates Its Own Expression^*

Pedro J. Cejas, Louise M. Carlson, Jian Zhang¶, Swami Padmanabhan||, Despina Kolonias, Inna Lindner, Stephen Haley¶, Lawrence H. Boise¶, and Kelvin P. Lee¶**

From the Department of Microbiology and Immunology and ^¶Sylvester Comprehensive Cancer Center, University of Miami School of Medicine, Miami, Florida 33156 and the ^||Leukemia Section, Department of Medicine, Roswell Park Cancer Institute, Buffalo, New York 14263

Dendritic cells (DC) arise from a diverse group of hematopoietic progenitors and have marked phenotypic and functional heterogeneity. The signal transduction pathways that regulate the ability of progenitors to undergo DC differentiation, as well as the specific characteristics of the resulting DC, are only beginning to be characterized. We have found previously that activation of protein kinase C (PKC) by cytokines or phorbol esters drives normal human CD34⁺ hematopoietic progenitors and myeloid leukemic blasts (KG1, K562 cell lines, and primary patient blasts) to differentiate into DC. We now report that PKC activation is also required for cytokine-driven DC differentiation from monocytes. Of the cPKC isoforms, only PKC-II was consistently activated by DC differentiation-inducing stimuli in normal and leukemic progenitors. Transfection of PKC-II into the differentiation-resistant KG1a subline restored the ability to undergo DC differentiation in a signal strength-dependent fashion as follows: 1) by development of characteristic morphology; 2) the up-regulation of DC surface markers; 3) the induction of expression of the NFB family member Rel B; and 4) the potent ability to stimulate allo-T cells. Most unexpectedly, the restoration of PKC-II signaling in KG1a was not directly due to overexpression of the transfected classical PKC (, II, or ) but rather through induction of endogenous PKC- gene expression by the transfected classical PKC. The mechanism of this positive autoregulation involves up-regulation of PKC- promoter activity by constitutive PKC signaling. These findings indicate that the regulation of PKC-II expression and signaling play critical roles in mediating progenitor to DC differentiation.

Received for publication, January 11, 2005 , and in revised form, April 1, 2005.

^* This work was supported by National Institutes of Health Grants CA85208 and CA95829. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Both authors contributed equally to this work.

^** To whom correspondence should be addressed: Dept. of Microbiology and Immunology, University of Miami School of Medicine, Papanicolaou Bldg., Rm. 211, 1550 NW 10th Ave., Miami, FL 33136. Tel.: 305-243-1044; Fax: 305-243-4409; E-mail: klee{at}med.miami.edu.

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