Investigating the Role of PCM1 and Mib1 in Regulating Ciliogenesis and in Prostate Cancer
Abstract
The purpose of this research is to reveal the relationship between assembly of the primary cilium and prostate cancer by investigating two centrosomal proteins, pericentriolar material 1 (PCM1) and Mind bomb 1 (Mib1), and to test the possibility that these proteins can serve as robust prostate cancer biomarkers and, potentially, targets for drug discovery. The primary cilium serves as a cellular antenna, and this organelle inhibits cell proliferation. The loss of this key signaling organelle was reported in various cancers, including prostate cancer. Therefore, we hypothesize that the absence of a primary cilium can potentially trigger cell proliferation and prostate cancer development. Pericentiolar material 1 is essential for ciliogenesis, and the PCM1 gene is deleted in ~15% of prostate cancers. Our results indicate that ablation of pericentriolar material 1 leads to aberrant expression of its interacting partner, Mind bomb 1, an enzyme that is a negative regulator of ciliogenesis. Based on these data, we hypothesize that elevated levels of Mind bomb1 provoked by pericentriolar material 1 depletion in prostate cancer promote abnormal cell growth and malignancy by preventing the assembly of cilia. To test this hypothesis, we will investigate the impact of pericentriolar material 1 deletions in prostate cancer and determine whether there is a correlation between increased Mind bomb 1, the loss of cilia, and the stage of prostate tumor progression. Next, we will test whether pericentriolar material 1 depletion and aberrant levels of Mind bomb 1 promote prostate cancer development. Finally, we will investigate whether Mind bomb 1 removal induces ciliogenesis and inhibits growth of prostate cancer to determine the suitability of Mind bomb 1 as a target of anti-cancer drugs. Collectively through our research proposal, we will be able to understand a novel regulatory pathway in the formation of primary cilia and its implications in prostate cancer development. These efforts will ultimately allow us to devise innovative and effective therapeutic approaches against malignant prostate cancer. First, our investigation may allow us to find new biomarkers to detect cancer. In addition, since we are examining a "druggable" protein with enzymatic activity, our results could ultimately allow discovery of potential anti-cancer drugs for effective therapeutic approaches against malignant prostate cancer, which is a leading, fatal disease threatening the male population worldwide. During my doctoral studies and over the past 2 years, I have studied processes associated with the assembly and function of centrosomes and primary cilia. I have become very interested in diseases that result from deregulation of centrosome numbers and defects in the assembly of cilia. Therefore, I am working at the New York University School of Medicine Cancer Institute as a postdoctoral fellow under the supervision of Dr. Dynlacht and my co-mentor, Dr. Peng Lee, an expert in prostate pathology and cancer. This research fits well with my long-term career goal of pursuing prostate cancer research with translational potential. Support from this postdoctoral training fellowship would greatly help me to achieve my career goals. This fellowship will allow me to learn techniques in prostate cancer research by working closely with Dr. Lee. After my training as postdoctoral fellow, I will pursue a career as an independent principal investigator at an academic institution trying to further understand mechanisms of prostate tumorigenesis.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610392
Entities
People
- Lei Wang
Organizations
- Grossman School of Medicine
- United States Army