Submitted April 25, 2007
Accepted August 21, 2007
CD74 induces TAp63 expression leading to B cell survival
Frida Lantner, Diana Starlets, Yael Gore, Liat Flaishon, Ayala Yamit-Hezi, Rivka Dikstein, Lin Leng, Richard Bucala, Yossy Machluf, Moshe Oren, and Idit Shachar*
Department of Immunology, Weizmann Institute of Science, Rehovot, Israel
Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel
Department of Biological Chemistry, Weizmann Institute of Science, Rehovot, Israel
Department of Medicine, Yale University School of Medicine, New Haven, CT, United States
* Corresponding author; email: idit.shachar{at}weizmann.ac.il.
Most mature follicular B cells circulate within the periphery in a quiescent state, without actively contributing to an acute immune response. Lasting B cell persistence in the periphery is dependent on survival signals that are transduced by cell surface receptors. We recently demonstrated that cell surface CD74 controls mature B cell survival. Stimulation of cell surface CD74 leads to NF-
B activation, which enables entry of the stimulated B cells into the S phase, induction of DNA synthesis and cell division, and augments the expression of survival genes. In the present study, we investigated CD74 target genes, in order to determine the identities of the molecules whose expression is modulated by CD74, thereby regulating B cell survival. We report that CD74 activates the p65 member of the NF-B family, which in turn upregulates the expression of p53-related TAp63 proteins. TAp63 then binds and transactivates the Bcl-2 gene and induces the production of Bcl-2 protein, thereby providing the cells with increased survival capacity. Thus, the CD74/NF-B/TAp63 axis defines a novel anti-apoptotic pathway in mature B cells, resulting in the shaping of both the B cell repertoire and the immune response.
