Kimberly Uchida, University of Utah
Bioengineering and Oncological Sciences
Programmed cell death 4 (PDCD4) loses its function as a tumor suppressor when co-expressed with a specific binding partner, protein arginine methyltransferase-5 (PRMT5). A better understanding of the regulation of PDCD4-PRMT5 interaction may lead to cancer therapies targeted at restoring the tumor suppressive function of PDCD4. Using Xenopus laevis (frog) eggs to generate extract trapped in either interphase or mitosis, we found that PDCD4-PRMT5 interaction is regulated by the cell cycle. Full-length PDCD4 bound PRMT5 more robustly in interphase than in mitosis. However, a truncated version of PDCD4, that retained the PRMT5 binding site, bound PRMT5 equally in interphase and mitosis. These results indicate that there may be a component of full-length PDCD4 that occludes the PRMT5 binding site in mitosis. Furthermore, we found that both full-length and the truncated PDCD4 are preferentially phosphorylated in mitosis, but preferentially methylated in interphase. From these results we speculate that phosphorylation of PDCD4 in mitosis allows PDCD4 to fold upon itself and effectively block the PRMT5 binding site. Additionally, phosphorylation may prevent methylation even when PRMT5 can bind PDCD4, explaining the lack of PDCD4 methylation in mitosis. Such an inhibitory mechanism may be useful in therapeutically restoring the tumor suppressive function of PDCD4. Future research will be aimed towards completing our understanding of PDCD4-PRMT5 interaction in the cell cycle, such as proving our model in human cells.