Date of Award

2013

Degree Type

Dissertation

Degree Name

Ph.D.

Department

Biological Sciences

First Advisor

Lisa A. Porter

Keywords

Biological sciences, Health and environmental sciences, Cell cycle regulation, Cell fate, Central nervous system, Tumor-initiating cells

Rights

CC BY-NC-ND 4.0

Abstract

Mitotically active cells at the sites of neurogenesis and primitive cells of the sympathetic nervous system are speculated to act as a source of stem-like tumor initiating cells (TICs) in neural cancers like glioma and neuroblastoma. Understanding how normal neural stem and progenitor cells regulate their growth and differentiation decisions throughout life is of high priority. Spy1 (Speedy, Spdya, RINGO) is a unique cyclin-like protein that enhances proliferation by activating the cyclin dependent kinase 2 (CDK2) and promoting the degradation of the CDK inhibitor p27 Kip1 . Spy1 levels are tightly regulated during developmental processes and Spy1 upregulation has been reported in several types of cancer including human glioma. Spy1 effectors, CDK2 and p27 Kip1 , play a regulatory role in many developmental events including neurogenesis and these effectors are aberrantly regulated in several aggressive forms of cancer. My study sought to investigate the role of Spy1 in regulating proliferation, self-renewal and differentiation processes of neural progenitors and to determine the implications of this protein in neural cancers. My work demonstrates that Spy1 is an important driver of the CD133+ brain tumour initiating cell (BTIC) population. Spy1 controls the ability of BTICs to symmetrically divide and the amplification of the SPDYA gene loci correlates with poor patient prognosis. We show that Spy1 is expressed at high levels in neurogenic regions of the adult brain and the overexpression of Spy1 significantly increases cell proliferation parameters including the number and longevity of neurospheres. These data demonstrate for the first time that the Spy1/RINGO family plays an important role in neural fate decisions and that overexpression of Spy1 is a driving factor in specific forms of neural cancer.

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