Nagi G. Ayad, Ph.D.
Associate Professor of Psychiatry
Description of Research
Dr. Ayad studies cell cycle transitions in the developing nervous system. Dr. Ayad’s laboratory identified essential proteins required for controlling mitotic entry and exit and also demonstrated that cell cycle proteins are present and active in the developing nervous system and fully differentiated neurons. Specifically, the research group uncovers the mechanism through which the Anaphase Promoting Complex/Cyclosome (APC/C) and other cell cycle regulators such as Casein Kinase 1, Fblx15, and Wee 1 control cell proliferation, cycle exit, and differentiation. These neural progenitor cell cycle proteins are kinases and ubiquitin ligases that are targets in cancer. Thus, the Ayad laboratory is searching for novel molecular pathways that control neural development and are targets in cancer. This is accomplished using a multi-disciplinary approach that utilizes whole genome siRNA, cDNA, and small molecule cell-based screens to develop therapies directed against cancer.
Although a great deal is known about the regulatory mechanisms controlling cell cycle transitions, gaps in our understanding persist. For instance, one of the most important decisions a dividing cell must make is whether to proliferate or exit the cell cycle. Yet it is not fully understood how this decision is made. The Ayad laboratory has previously uncovered a requirement for the APC/C-Cdh1 complex for exiting the cell cycle. It demonstrated that APC/C-Cdh1 induces degradation of Skp2, which allows for p27 accumulation, and cell cycle exit of cerebellar granule cells in the developing cerebellum (Harmey et al., 2009). This finding is in keeping with studies in other model systems demonstrating that achieving a certain threshold level of p27 is important for initiating cell cycle exit of neuronal precursors, muscle cell precursors, and lens epithelial cells (Li et al., 2007), (Wu et al., 2007). The Ayad laboratory is building upon these findings to discover novel small molecules that are targets in medulloblastoma, glioblastoma, and other cancers.
One of the main lines of investigation from the Ayad laboratory is to understand the role of Casein kinase 1 (CK1) in proper cell cycle progression and exit in the developing nervous system. The Ayad laboratory has identified a novel CK1/inhibitor (FKL135), which is more potent than previously described inhibitors. FKL135 potently inhibits cerebellar granule cell proliferation. Dr. Ayad’s laboratory is using this inhibitor to assay the contribution of CK1 and CK1 to cerebellar granule cell neurogenesis. In addition, in collaboration with Scripps Florida the Ayad laboratory is modifying FKL-135 to make it more selective for CK1 over other kinases. Already modified versions of this inhibitor have been identified and have potently inhibited proliferation of various cancer cell lines in vitro and in vivo. Ongoing studies will test the effects of these new inhibitors in mouse models of medulloblastoma and gliobalstoma since recent exciting PK studies have demonstrated that these molecules cross the blood-brain barrier.
- Identified two novel cell cycle proteins Tome-1 and sororin, which are overexpressed in multiple cancers
- Demonstrated that the APC-Cdh1 complex targets the oncogene Skp2 for degradation
- Discovered a requirement for the tumor suppressor protein complex APC-Cdh1 for exiting the cell cycle in cerebellar granule cell progenitors, which are the cells that give rise to the most prevalent pediatric brain tumor, medulloblastoma
- Demonstrated that the cell cycle protein Wee1 is targeted for degradation via its activation domain
- Developed a cell-based high-throughput means of identifying parts of proteins required for protein turnover
- Developed ultra-highthroughput means of identifying small molecule inhibitors of Wee1 destruction
- Identified highly specific small molecule inhibitors of GSK-3 and CK-1 through collaborations with Scripps Florida. These molecules are currently being tested in mouse models of medulloblastoma and glioblastoma
Selected Cancer-Related Publications
- Clarke J, Penas C, Pastori C, Komotar RJ, Bregy A, Shah AH, Wahlestedt C, Ayad NG. Epigenetic pathways and glioblastoma treatment. Epigenetics 8:,2013 Read more »