Date

6-2014

Document Type

Dissertation

Degree Name

Ph.D.

Institution

Oregon Health & Science University

Abstract

Reversible protein phosphorylation plays an important role in regulating cellular signaling and deregulation of this mechanism can contribute to many aberrant cellular behaviors, including many cancers.

The Protein Phosphatase 2A (PP2A), is one of the major phosphatases in the cell that has a tumor suppressor function through its regulation of c-MYC and other key signaling pathways. PP2A is a critical negative regulator of c-MYC through its ability to dephosphorylate Serine62. The c-MYC oncoprotein is stabilized and activated by phosphorylation at Serine 62 (phosphoS62-MYC) in many cancers. How PP2A is deregulated in cancer remains an ongoing research topic. The overall objective of this thesis is to test the hypothesis that PP2A function is required for normal cell homeostasis and its activity is suppressed in cancers by overexpression of cellular oncoproteins and targeting these inhibitors can reactivate PP2A and therefore modulate downstream signaling such as c-MYC.

In chapter 2, I show that two endogenous inhibitors of PP2A, the SET oncoprotein and CIP2A, are overexpressed in breast cancer and inhibition of either SET or CIP2A reduces the tumorigenic potential of breast cancer cell lines both in vitro and in vivo. Treatment of breast cancer cells with OP449, a novel SET antagonist, decreases the tumorigenic potential of breast cancer cells and induces apoptosis. I show that this is, at least in part, due to decreased hosphoS62-MYC and reduced c-MYC activity and target gene expression. Taken together these results show that PP2A activity is deregulated in breast cancer by SET or CIP2A and reactivation of PP2A, either through inhibiting SET or potentially CIP2A, can be a novel anti-tumor strategy to posttransnationally target c-MYC in breast cancer.

In chapter 3, I characterize a mouse model for B56α deletion. The PP2A oloenzyme has 3 subunits: a catalytic subunit, a structural subunit, and a variable regulatory (B) subunit, which directs PP2A to specific targets. Because loss of the regulatory subunit B56α was shown to be required for human cell transformation and that B56α negatively regulates c-MYC, we generated a novel mouse model of B56α knockout. I found that although the knockout of the B56α gene was in the whole body, the primary phenotypic effects of B56α loss were spontaneous skin lesion formation and increased immune cell infiltrations in the spleen and liver. I show that phosphoS62-MYC and its target gene Cdk4 are increased in these skin lesions. Because B56α negatively regulates many oncogenes such as c-MYC and β–catenin, our model suggests that B56α is important for homeostasis of cells and B56α loss could lead to increased activity of these oncogenes and subsequently aberrant cell proliferation.

Identifier

doi:10.6083/M4QJ7G1R

Division

Cancer Biology Program

School

School of Medicine

Available for download on Monday, September 04, 2017

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