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Tumor Suppressor Functions of the Zebrafish ink4a/b: A Novel Cyclin Dependent Kinase Inhibitor

by
Stephani A Davis
B.S., Delaware State University 2008

Thesis Advisor: Hatem Sabaawy, M.D., Ph.D.
Graduate Program in Molecular & Cellular Pharmacology

Rutgers RWJMS Research Tower
Deanís Conference Room R-123
Piscataway

Tuesday, April 1, 2014
3:00 p.m.


Abstract

The INK4B-ARF-INK4A locus encodes for two cyclin-dependent kinase inhibitors, p15 (INK4b) and p16 (INK4a) and a regulator of the p53 pathway, ARF. All of three products play a pivotal role in tumor suppression and are frequently deleted or inactivated in a wide spectrum of human cancers. Despite the critical role of the mammalian INK4B-ARF-INK4A locus in tumor suppression, its counterpart in zebrafish has not yet been characterized. Zebrafish offers several unique advantages as vertebrate system to model human cancers, specifically because of the high fecundity, the ease of performing high-throughput screens, and the genetic conservation with mammals. We identified a syntenic zebrafish ink4a/b locus that consists of a single gene orthologous to both mammalian CDKN2A (INK4A) and CDKN2B (INK4B). Utilizing morpholino targeted knockdown and zebrafish mutants for the ink4a/b gene, we have developed a zebrafish model for tumorigenesis. Cross-species expression analysis of ink4a/b demonstrates that the zebrafish ink4a/b gene has a functionally conserved role as a cyclin-dependent kinase inhibitor. We find that ink4a/b deficient embryos have decreased levels of senescence and also display significantly higher levels of apoptosis than controls. We determined that the apoptosis associated with ink4a/b deficiency is p53-dependent. Furthermore, ink4a/b deficiency led to significantly lower survival rates, both overall and upon radiation. Ink4a/b deficient zebrafish had splenomegaly, increased lymphocyte proliferation, and developed spontaneous tumors including metastatic melanoma, osteosarcoma, hepatocellular adenoma, leukemia and myelodysplastic disorders. Thus, the zebrafish ink4a/b protein functions as a tumor suppressor similarly to the human p15INK4B and p16INK4A. The combined deficiency of ink4a/b and p53 accelerates the latency of tumor initiation and broadens the tumor spectrum including the formation of retinoblastoma. Collectively, the zebrafish ink4a/b model cancer model provides a platform to perform large-scale screens for small molecules that modulate tumorigenesis, and permit defining the genetic pathways of CDKN2A- and CDKN2B-mediated tumor suppression.


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