G5 Doctoral dissertation (article)

A Systems Biology Analysis of PP2A Functions in Cancer Cells




List of Authors: Kauko Otto

Publisher: University of Turku

Place: Turku

Publication year: 2017

ISBN: ISBN 978-951-29-6686-8

eISBN: ISBN 978-951-29-6687-5

URL: http://urn.fi/URN:ISBN 978-951-29-6687-5


Abstract

Cancer is
characterized by aberrant activation of phosphorylation signalling cascades.
However, despite the critical role of phosphatases in protein phosphorylation,
their contribution to cancer cell signalling is only emerging. Notably, Protein
phosphatase 2A (PP2A) has a well-established tumor suppressor function but it
is poorly understood which of its many targets are relevant for this function.
This is partly due to the wide range of activities that PP2A participates in
and partly due to the fact that PP2A activity regulation, as well as the
deregulation in cancer, occurs via many auxiliary subunits and endogenous
inhibitor proteins.

In this
MD-PhD thesis, we have used various systems biology approaches, including
phosphoproteomics, high throughput drug sensitivity screening, and
transcriptomics to study the functions of the most frequently mutated PP2A
subunit, PPP2R1A, as well as three of its endogenous inhibitor proteins, CIP2A,
PME1, and SET in cancer cells.

This study
demonstrates that PP2A reactivation is poorly tolerated by several types of
cancer cells and results in downregulation of multiple oncogenic pathways, as
well as induction of senescence. Specifically, CIP2A is a regulator of MYC transactivation
in basal type breast cancers and our results indicate multiple cooperative
mechanisms by which PP2A regulates MYC. Analysis of PP2A dephosphorylome also
provided novel insights into general organization of phosphorylation signalling
and emphasized the role of PP2A inhibition in the nucleus.












By
combining the phosphoprotemics data with cancer cell responses to over 300
drugs, we have identified mechanistically distinct types of interactions
between drug sensitivity and PP2A activity. We further validated that inhibition
of PP2A in KRAS mutant lung cancers confers resistance to MAPK pathway
inhibitors including the combination of Raf and MEK inhibitors.


Last updated on 2021-24-06 at 10:45