Protein kinase Cδ (PKCδ) deficiency causes autoimmune pathology in humans and mice and is crucial for the maintenance of B cell homeostasis. However, the mechanisms underlying autoimmune disease in PKCδ deficiency remain poorly defined. Here, we address the antigen-dependent and -independent roles of PKCδ in B cell development, repertoire selection, and antigen responsiveness. We demonstrate that PKCδ is rapidly phosphorylated downstream of both the B cell receptor (BCR) and the B cell-activating factor (BAFF) receptor. We found that PKCδ is essential for antigen-dependent negative selection of splenic transitional B cells and is required for activation of the proapoptotic Ca²⁺-Erk pathway that is selectively activated during B cell-negative selection. Unexpectedly, we also identified a previously unrecognized role for PKCδ as a proximal negative regulator of BCR signaling that substantially impacts survival and proliferation of mature follicular B cells. As a consequence of these distinct roles, PKCδ deficiency leads to the survival and development of a B cell repertoire that is not only aberrantly autoreactive but also hyperresponsive to antigen stimulation.

Most human tumors harbor mutations that misregulate the early phases of the cell cycle. Here, we summarize genetic evidence,mostly obtained in our laboratory using strains of gene-targeted mice, that provides direct experimental support for arole of Cdk4 in tumor development. Moreover, these genetic studies challenge some well-established concepts regarding therole of Cdks during the early phases of the cell cycle. For instance, they have illustrated that Cdk4 and Cdk6 are not essentialfor cell division during embryonic development except in the hematopoietic system. More surprisingly, mice lackingCdk2 survive for over 2 years without detectable abnormalities except in their germ cells, indicating that Cdk2 is essentialfor meiosis but dispensable for the normal mitotic cell cycle. Cdk2 is also dispensable for cell cycle inhibition and tumor suppressionby the Cip/Kip inhibitors, p21^Cip1 and p27^Kip1. These observations have important implications not only to understandcell cycle regulation, but also to validate Cdks as potential targets for the development of therapeutic strategies to blockproliferation of tumor cells.