Cancer and Metastasis Reviews 1L3: 411M31.I994. © 1994 KluwerAcademic Publishers. Printedin the Netherlands. Regulation of protein kinase C and role in cancer biology Gerard C. Blobe, Lina M. Obeid and Yusuf A. Hannun Divisions of Hematology/Oncology and Geriatrics, Departments of Medicine and Cell Biology, Duke Uni- versity Medical Center, Durham, NC 27710, USA Key words: protein kinase C, isoenzymes, cancer, differentiation Abstract Protein kinase C (PKC) is a family of closely related lipid-dependent and diacyglycerol-activatedisoenzymes known to play an important role in the signal transduction pathways involved in hormone release, mitogenesis and tumor promotion. Reversible activation of PKC by the second messengers diacylglycerol and calcium is an established model for the short term regulation of PKC in the immediate events of signal transduction. PKC can also be modulated long term by changes in the levels of activators or inhibitors for a prolonged period or by changes in the levels of functional PKC isoenzymes in the cell during development or in response to hormones and/or differentiation factors. Indeed, studies have indicated that the sustained activation or inhibition of PKC activity in vivo may play a critical role in regulation of long term cellular events such as proliferation, differentiation and tumorigenesis. In addition, these regulatory events are important in colon cancer, where a decrease in PKC activators and activity suggests PKC acts as an anti-oncogene, in breast cancer, where an increase in PKC activity suggests an oncogenic role for PKC, and in multidrug resistance (MDR) and metastasis where an increase in PKC activity correlates with increased resistance and metastatic potential. These studies highlight the importance and significance of regulation of PKC activity in vivo. Introduction Protein kinase C was initially discovered and char- acterized by Nishizuka and co-workers in 1977 as a proteolytically activated kinase [1]. PKC was then further characterized as a calcium and phospholipid (PL) dependent kinase [2]. Two major discoveries in the early 1980's established the importance of PKC in signal transduction and tumor promotion. The first was that the basal activity of PKC was stimulated by diacylglycerol (DAG), a product of the phosphatidylinositol (PI) cycle [3]. Shortly thereafter came the discovery that PKC was activa- ted by and was the major intracellular receptor for the tumor promoting phorbol esters [4, 5]. Other work in the early 1980's clarified the mechanisms by which calcium, phospholipid and DAG activated PKC in vitro, and led to the characterization of many activators, inhibitors, and substrates for PKC. At the same time the phenomena of autophospho- rylation, pseudosubstrate inhibition, translocation and down regulation of PKC were also elucidated and studied. Much of the early work characterizing the enzy- matic regulation of PKC assumed that PKC was a single enzymatic entity, however, cloning of PKC has revealed that PKC is a family of closely related isoenzymes; products of distinct genes (with the ex- ception of PKC ~3Iand 13IIwhich are derived via al- ternative splicing of a common gene). As of this date eleven different PKC isoenzymes have been cloned including the calcium-dependent isoen- zymes, cq 13I 13II, and 7, the calcium-independent isoenzymes 5, ~, rh e and tx and the atypical isoen- zymes ~ and i()~). The PKC isoenzymes are closely related structur-