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Dissertation/Thesis Abstract

Targeting Cyclin Dependent Kinases in Embryonic Stem Cells and Cancer
by Mullin, Noelle Huskey, Ph.D., University of California, San Francisco, 2013, 134; 3558431
Abstract (Summary)

Cyclin dependent kinases (Cdks) are a family of conserved serine/threonine kinases that regulate cell cycle progression in mammalian cells. Activation of individual Cdks at distinct phases of the cell cycle ensures the proper timing and coordination of cell cycle events. Over the past decade, gene knockout models combined with studies using small molecule kinase inhibitors have shown that the effect of individual Cdk inactivation is highly dependent on cellular and genetic context. Here we examine the effect of Cdk1 inhibition on embryonic stem (ES) cells. Additionally, we develop a chemical genetic approach that allows for the selective inhibition of Cdk2 in multiple cell and cancer types.

Embryonic stem (ES) cells are an attractive source for stem cell therapies due to their rapid proliferation and capacity for differentiation. A limitation in the field of regenerative medicine however, is the propensity for ES cells to form teratomas when transplanted in vivo. Selective depletion of undifferentiated cells during regeneration therapies could reduce the carcinogenic risks of these procedures. We show that inhibiting Cdk1 results in the activation of a DNA damage response, nuclear p53 stabilization, and induction of pro-apoptotic p53 target genes in ES but not differentiated cells. Furthermore we show that clinically relevant Cdk1 inhibitors prevent formation of ES cell-derived tumors and inhibit growth of established ES cell-derived teratomas in vivo. Our data demonstrate that ES cells are uniquely sensitive to Cdk1 inhibition, and identify Cdk1 as a pharmacological target that could increase the safety of regeneration therapies. In an independent project, we use a chemical-genetic approach to achieve selective inhibition of Cdk2 kinase activity using an analog sensitive (AS) allele. We show that inhibition of Cdk2 kinase activity slows proliferation of non-transformed cells, whereas siRNA knockdown of Cdk2 does not, highlighting the differences between these approaches. We also show that Cdk2 inhibition attenuates anchorage-independent growth of transformed cells. Finally, we develop a Cdk2-AS mouse model that will allow for the acute inhibition of Cdk2 in a variety of cell types and cancer models. Together, these results enhance our understanding of the effects of Cdk inhibition in defined cellular and genetic contexts.

Indexing (document details)
Advisor: Goga, Andrei
Commitee: Blelloch, Robert, Goga, Andrei, Morgan, David O., Oakes, Scott A.
School: University of California, San Francisco
Department: Biomedical Sciences
School Location: United States -- California
Source: DAI-B 74/08(E), Dissertation Abstracts International
Subjects: Molecular biology, Cellular biology, Oncology
Keywords: Analog sensitivity, Cancer, Cell cycle, Cyclin dependent kinase, Stem cells
Publication Number: 3558431
ISBN: 978-1-303-02876-2
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