Elucidating the effect of polycomb homologues, BMI1 and MEL18, on the E3 ubiquitin ligase activity of RING1A and RNF2
Authors:Leslie Rabena, Liza Ragasa
Mentor:Luiza Nogaj, Associate Professor of Biology , Mount St. Mary's College
The Polycomb proteins (PcG) function as transcriptional repressors and are thought to prevent the transcription of tumor suppressor genes such as p16. The p16 protein is known to prevent the proliferation of cell growth and directs the cell into apoptosis. However, the mechanism of Polycomb-mediated silencing of p16 and its connection to prostate cancer progression is still not well understood. Polycomb complexes are composed of many proteins, Bmi-1, Mel 18, Ring1A, and Rnf2 among them. Previous work suggests that Ring1A and Rnf2 are ubiquitin ligases and their activity is regulated by Bmi1 and Mel18 (Elderkin et al., 2007, Wei et al., 2006). We study the role of the Polycomb complexes on the progression of prostate cancer. We examined the levels of Bmi1, Mel18, Ring1A, and Rnf2 in biopsy samples from different stages of prostate cancer. We have found that RING1A/B levels remain the same throughout all stages of prostate cancer progression. However, MEL18 and BMI1 are inversely present/absent. In the tissue of malignant tumors, there is an over expression of BMI1 and under expression of MEL18. This suggests that the dynamic between PRC1 proteins changes during cancer progression. We propose that the low levels of MEL18 and high levels of BMI1 are affecting the ubiquitin ligase activity of RING1A/B—increasing their ability to prevent p16 expression. In order to support this hypothesis, we are studying the ubiquitin ligase activity of RING1A/B on histone H2A in the presence and absence of BMI1 and MEL18. We suspect that either BMI1 is activating the ubiquitin ligase activity of RING1A/B in cancer cells or MEL18 is inhibiting this reaction in normal tissue. Our findings will help elucidate the relationship between PCR1 and p16 in cancer development.