Abstract 2547: Protein kinase C epsilon and protein kinase C delta, which are linked to skin carcinogenesis, associate with heat shock protein 90 beta
Authors: Haque Absarul , Jamal Mohammad S. , Meske Louise , Hafeez Bilal B. , Verma Ajit K. 
Published: August 2012

Abstract
Protein kinase C (PKC), a family of eleven (≥, αI, αII, β, α, β, α, β, α, β, α) phospholipid-dependent serine/threonine protein kinases, exhibits functional diversity in its signals to a variety of cellular functions including cell proliferation, differentiation, apoptosis and carcinogenesis. At least six PKC isoforms (≥, β, α, β, ≤ and α) are expressed in both mouse and human epidermis. To determine the in vivo functionality of PKC ≤ and β, in mouse skin carcinogenesis, we generated transgenic mice overexpressing an epitope tagged PKC (δ or ∈)) under the control of human keratin 14 promoter. The susceptibility of PKC (δ or ∈) overexpressing mice to skin carcinogenesis was determined by initiation with DMBA and promotion with TPA. PKC∈ and PKC∈ transgenic mice exhibited different responses to skin tumor promotion by TPA. PKC∈ suppressed both formation of skin papillomas and carcinomas. PKC∈ transgenic mice developed only squamous cell carcinomas, which could metastasize. PKC∈ expression level also dictated the susceptibility of mice to the development of SCC by chronic exposure (2 kJ/m2 thrice weekly) to ultraviolet radiation (UVR). As compared to wild-type littermates, PKC∈ over-expressing transgenic mice exhibited decrease in tumor latency by 12 weeks and a 3-fold increase in tumor multiplicity. To find clues about the mechanism by which PKC isoforms (δ or ∈) may mediate skin carcinogenesis, we found that PKC (δ or ∈) interacts with heat shock protein (Hsp) 90α. Hsp90 is a ubiquitous molecular chaperone, which plays a key role in the folding, activation and assembly of a range of structurally and functionally different client proteins (e.g., telomerase, nuclear hormone receptors, protein kinases) in eukaryotic cells. Hsp90 exhibits a high degree of specificity towards client proteins. In the present experiments, mice were exposed to either single or chronic UVR treatments, emitted by Kodacel-filtered FS-40 sun lamps (approximately 60% UVB and 40% UVA). In reciprocal immunoprecipitation/blotting experiments, PKC∈ and ≤ associated with Hsp90α in intact mouse epidermis in vivo. The association of PKC∈ and ≤ with Hsp90α was further enhanced after UVR exposure of mice. We also determined the interaction of Hsp90α with other PKC isoforms. Hsp90α did not interact with PKC∈, PKC∈ or PKC∈. Hsp90α is a core component of multiprotein complex involving several collaborating chaperons (e.g., Hsp70/Hsp40, Hop/sti1, Cdc37, p21). In reciprocal immunoprecipitation/blotting experiments, PKC∈ also interacted with Hsp70 but the interaction was not as dramatic as with Hsp90α. In summary, association of Hsp90α with its client PKC∈ and ≤ may be essential for both their maturation into a signaling-competent enzyme and enzyme stability. Association of Hsp90α with PKC∈ and ≤ may be critical for their signals to skin carcinogenesis. (Support: NIH Grant CA 35368)
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2547. doi:1538-7445.AM2012-2547