Diacylglycerol Signaling

8 PKC and Control of the Cell Cycle
progression in a highly context-dependent manner. The complexity of the cell
cycle-specific effects of these molecules is well exemplified by studies in 3Y1
fibroblasts, where PKCd stimulates G 1 /S progression while potently inhibiting
mitosis (Kitamura et al. 2003). Fewer studies have addressed the roles of other
members of the PKC family. Thus, although PKCbII and e generally appear to play
a cell cycle stimulatory role, a few studies point to additional complexity. In view
of the inherent drawbacks in current approaches used to understand PKC isozymespecific
functions (i.e., overexpression studies, use of nonselective agonists and
inhibitors, analysis of transformed cell lines), it may be helpful to focus future studies
on gaining a better understanding of the expression and activation of these
molecules in unperturbed tissue systems, and using this information to guide subsequent
mechanistic analyses. In seeking deeper insight into the biological functions
of individual PKCs, it will also be critical to understand the regulatory inputs
and downstream events induced by PKC activation, and to identify target proteins
that are modulated by PKCs in vivo.
Acknowledgments I would like to thank past and present members of my laboratory for their
contributions to the study of PKC and control of cell cycle progression. I also thank Drs. Adrian
Black and Debora Kramer for critical reading of the manuscript and Dr. Adrian Black and
Margaret Frey for the artwork. I apologize to many colleagues whose work was not cited due to
space limitations. Work in my laboratory is supported by NIH grants DK54909, DK60632, and
CA16056.
References
Abraham, C., Scaglione-Sewell, B., Skarosi, S. F., Qin, W., Bissonnette, M., & Brasitus, T. A.
(1998). Protein kinase C alpha modulates growth and differentiation in Caco-2 cells.
Gastroenterology, 114, 503–509.
Acevedo-Duncan, M., Patel, R., Whelan, S., & Bicaku, E. (2002). Human glioma PKC-iota and
PKC-betaII phosphorylate cyclin-dependent kinase activating kinase during the cell cycle. Cell
Prolif, 35, 23–36.
Acs, P., Beheshti, M., Szallasi, Z., Li, L., Yuspa, S. H., & Blumberg, P. M. (2000). Effect of a
tyrosine 155 to phenylalanine mutation of protein kinase cdelta on the proliferative and tumorigenic
properties of NIH 3T3 fibroblasts. Carcinogenesis, 21, 887–891.
Acs, P., Wang, Q. J., Bogi, K., Marquez, A. M., Lorenzo, P. S., Biro, T., et al. (1997). Both the
catalytic and regulatory domains of protein kinase C chimeras modulate the proliferative properties
of NIH 3T3 cells. J Biol Chem, 272, 28793–28799.
Afrasiabi, E., Ahlgren, J., Bergelin, N., & Tornquist, K. (2008). Phorbol 12-myristate 13-acetate
inhibits FRO anaplastic human thyroid cancer cell proliferation by inducing cell cycle arrest
in G1/S phase: evidence for an effect mediated by PKCdelta. Mol Cell Endocrinol, 292,
26–35.
Agell, N., Jaumot, M., Rodriguez-Vilarrupla, A., Brun, S., Abella, N., Canela, N., et al. (2006).
The diverging roles of calmodulin and PKC in the regulation of p21 intracellular localization.
Cell Cycle, 5, 3–6.
Akashi, M., Osawa, Y., Koeffler, H. P., & Hachiya, M. (1999). p21WAF1 expression by an activator
of protein kinase C is regulated mainly at the post-transcriptional level in cells lacking p53:
important role of RNA stabilization. Biochem J, 337(Pt 3), 607–616.
177