The cytoplasmic Purkinje onconeural antigen cdr2 down-regulates c-Myc function: implications for neuronal and tumor cell survival

Paraneoplastic cerebellar degeneration (PCD) is a disorder in which breast or ovarian tumors express an onconeural antigen termed cdr2, which normally is expressed in cerebellar Purkinje neurons. This leads to an immune respo nse to cdr2 that is associated with tumor immunity and autoimmune cerebella r degeneration. We have found that cdr2, a cytoplasmic protein harboring a helix-leucine zipper (HLZ) motif, interacts specifically with the HLZ motif of c-Myc. Both proteins colocalize in the cytoplasm of adult cerebellar Pu rkinje neurons, and coimmunoprecipitate from tumor cell lines and cerebella r extracts. cdr2 down-regulates c-Myc-dependent transcription in cotransfec tion assays, and redistributes Myc protein in the cytoplasm. Disease antise ra from six of six PCD patients specifically blocked the interaction betwee n cdr2 and c-Myc in vitro. These data indicate that cdr2 normally sequester s c-Myc in the neuronal cytoplasm, thereby down-regulating c-Myc activity, and suggest a mechanism whereby inhibition of cdr2 function by autoantibodi es in PCD may contribute to Purkinje neuronal death.