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A tumor suppressor role for PP2A-B56α through negative regulation of c-Myc and other key oncoproteins

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Abstract

Loss or inhibition of the serine/threonine protein phosphatase 2A (PP2A) has revealed a critical tumor suppressor function for PP2A. However, PP2A has also been shown to have important roles in cell cycle progression and survival. Therefore, PP2A is not a typical tumor suppressor. This is most likely due to the fact that PP2A represents a large number of different holoenzymes. Further understanding of PP2A function(s), and especially its tumor suppressor activity, will depend largely on our ability to determine specific targets for these different PP2A holoenzymes and to gain an understanding of how these targets confer tumor suppressor activity or contribute to cell cycle progression and cell survival. Recent work has identified c-Myc as a target of the PP2A holoenzyme, PP2A-B56α. This holoenzyme also negatively regulates β-catenin expression and modulates the anti-apoptotic activity of Bcl2, thus characterizing PP2A-B56α as a tumor suppressor PP2A holoenzyme. This review will focus on the role of PP2A-B56α in regulating c-Myc and will place this tumor suppressor activity of PP2A within the context of its other tumor suppressor functions. Finally, the mechanism(s) through which PP2A-B56α tumor suppressor activity may be lost in cancer will be discussed.

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Abbreviations

APC:

adenomatous polyposis coli

Bcl2:

B-cell lymphoma 2

Cdc25:

cell division cycle 25

c-Myc:

cellular Myelocytomatosis

DARPP-32:

dopamine- and cAMP-regulated phosphoprotein 32 kD

DVL:

dishevelled

ERK:

extracellular receptor kinase

FLD:

flexible loop domain

GSK3β:

glycogen synthase kinase 3β

HAND1:

heart and neural crest derivatives expressed 1

HEAT:

huntingtin-elongation-A subunits-TOR-like

hTERT:

human telomerase reverse transcriptase

MAPK:

mitogen activated protein kinase

Mdm2:

mouse double minute 2

MIZ1:

Myc interacting zinc-finger 1

PI3K:

phosphoinositide-3-kinase

Pin1:

protein (peptidylprolyl cis/trans isomerase) NIMA-interacting 1

PP2A:

protein phosphatase 2A

PTEN:

phosphatase and tensin homolog

S:

serine

SCF:

Skp/Cullin/F-box

SV40:

Simian virus 40

T:

threonine

TCF:

T cell specific factor

Wnt:

wingless/Int

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  1. Department of Molecular and Medical Genetics, Oregon Health & Sciences University, 3181 SW Sam Jackson Park Rd., L103A, Portland, OR, 97239, USA

    Hugh K. Arnold & Rosalie C. Sears

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Arnold, H.K., Sears, R.C. A tumor suppressor role for PP2A-B56α through negative regulation of c-Myc and other key oncoproteins. Cancer Metastasis Rev 27, 147–158 (2008). https://doi.org/10.1007/s10555-008-9128-9

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