Date of Award
Doctor of Philosophy (PhD)
Darnell Robert Laboratory
Paraneoplastic cerebellar degeneration (peD) is a remote effect of breast and ovarian cancer on the nervous system. It is believed to arise when these tumors ectopically express a neuron-specific protein, thereby initiating an anti-tumor immune response that subsequently develops into a neuronal degeneration. Three cerebellar degeneration related (cdr) genes encoding putative antigens were previously identified using PCD antisera. We have demonstrated that cdr2, which encodes a cytoplasmic coiled-coil leucine zipper protein, is the only cdr gene expressed in PeD-associated tumors, and is therefore the true PCD tumor antigen. We have isolated the mouse cdr2 homologue and examined expression of the mRNA and protein in adult tissues. The cdr2 antigen is detected only in the brain and testis, both considered to be immune-privileged sites. Within the nervous system, cdr2 is expressed predominantly in the cerebellum and brainstem, the regions most affected in PCD. These findings are therefore consistent with the proposed role of cdr2 in the autoimmune hypothesis for peD. While the cdr2 protein is detected only in brain and testis, the mRNA is expressed in almost all tissues, suggesting that cdr2 is regulated at a post-transcriptional level. In order to elucidate the function of the cdr2 gene product, we have performed protein-protein interaction studies. Using the coiled-coil leucine zipper domain of cdr2 in a yeast two-hybrid screen, we have identified c-Myc as a cdr2-binding protein. Immunohistochemical analysis of cerebellar cortex revealed that cdr2 and c-Myc colocalize exclusively to the cytoplasm of Purkinje neurons. We have found that the full length cdr2 and c-Myc proteins interact in vitro, and that this binding requires the basic helix-loophelix leucine zipper region of c-Myc. In addition, cdr2 represses c-Myc transcriptional activity in a transfected cell line. We conclude from these findings that the cdr2 antigen is a regulator of the oncoprotein c-Myc in cerebellar Purkinje neurons, and possibly in tumors.
Corradi, John Peter, "Characterization of the Paraneoplastic Cerebellar Degeneration Antigen Cdr2" (1997). Student Theses and Dissertations. 383.