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The protein phosphatase 2A regulatory subunit B55? is a modulator of signaling and microRNA expression in acute myeloid leukemia cells.

ABSTRACT: We recently discovered that the protein phosphatase 2A (PP2A) B55? subunit (PPP2R2A) is under-expressed in primary blast cells and is unfavorable for remission duration in AML patients. In this study, reverse phase protein analysis (RPPA) of 230 proteins in 511 AML patient samples revealed a strong correlation of B55? with a number of proteins including MYC, PKC ?, and SRC. B55? suppression in OCI-AML3 cells by shRNA demonstrated that the B subunit is a PKC? phosphatase. B55? does not target SRC, but rather the kinase suppresses protein expression of the B subunit. Finally, the correlation between B55? and MYC levels reflected a complex stoichiometric competition between B subunits. Loss of B55? in OCI-AML3 cells did not change global PP2A activity and the only isoform that is induced is the one containing B56?. In cells containing B55? shRNA, MYC was suppressed with concomitant induction of the competing B subunit B56? (PPP2R5A). A recent study determined that FTY-720, a drug whose action involves the activation of PP2A, resulted in the induction of B55? In AML cells, and a reduction of the B subunit rendered these cells resistant to FTY-720. Finally, reduction of the B subunit resulted in an increase in the expression of miR-191-5p and a suppression of miR-142-3p. B55? regulation of these miRs was intriguing as high levels of miR-191 portend poor survival in AML, and miR-142-3p is mutated in 2% of AML patient samples. In summary, the suppression of B55? activates signaling pathways that could support leukemia cell survival.

SUBMITTER: Ruvolo PP

PROVIDER: S-EPMC4165504 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature

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The protein phosphatase 2A regulatory subunit B55α is a modulator of signaling and microRNA expression in acute myeloid leukemia cells.

Ruvolo Peter P PP Ruvolo Vivian R VR Jacamo Rodrigo R Burks Jared K JK Zeng Zhihong Z Duvvuri Seshagiri R SR Zhou Liran L Qiu Yihua Y Coombes Kevin R KR Zhang Nianxiang N Yoo Suk Y SY Pan Rongqing R Hail Numsen N Konopleva Marina M Calin George G Calin George G Kornblau Steven M SM Andreeff Michael M

Biochimica et biophysica acta 20140521 9

We recently discovered that the protein phosphatase 2A (PP2A) B55α subunit (PPP2R2A) is under-expressed in primary blast cells and is unfavorable for remission duration in AML patients. In this study, reverse phase protein analysis (RPPA) of 230 proteins in 511 AML patient samples revealed a strong correlation of B55α with a number of proteins including MYC, PKC α, and SRC. B55α suppression in OCI-AML3 cells by shRNA demonstrated that the B subunit is a PKCα phosphatase. B55α does not target SRC ...[more]

PMID: 24858343

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Project description:The serine/threonine protein phosphatase 2A (PP2A) is a master regulator of the complex cellular signaling that occurs during all stages of mammalian development. PP2A is composed of a catalytic, a structural, and regulatory subunit, for which there are multiple isoforms. The association of specific regulatory subunits determines substrate specificity and localization of phosphatase activity, however, the precise role of each regulatory subunit in development is not known. Here we report the generation of the first knockout mouse for the Ppp2r2a gene, encoding the PP2A-B55? regulatory subunit, using CRISPR/Cas9. Heterozygous animals developed and grew as normal, however, homozygous knockout mice were not viable. Analysis of embryos at different developmental stages found a normal Mendelian ratio of Ppp2r2a-/- embryos at embryonic day (E) 10.5 (25%), but reduced Ppp2r2a-/- embryos at E14.5 (18%), and further reduced at E18.5 (10%). No live Ppp2r2a-/- pups were observed at birth. Ppp2r2a-/- embryos were significantly smaller than wild-type or heterozygous littermates and displayed a variety of neural defects such as exencephaly, spina bifida, and cranial vault collapse, as well as syndactyly and severe epidermal defects; all processes driven by growth and differentiation of the ectoderm. Ppp2r2a-/- embryos had incomplete epidermal barrier acquisition, associated with thin, poorly differentiated stratified epithelium with weak attachment to the underlying dermis. The basal keratinocytes in Ppp2r2a-/- embryos were highly disorganized, with reduced immunolabeling of integrins and basement membrane proteins, suggesting impaired focal adhesion and hemidesmosome assembly. The spinous and granular layers were thinner in the Ppp2r2a-/- embryos, with aberrant expression of adherens and tight junction associated proteins. The overlying stratum corneum was either absent or incomplete. Thus PP2A-B55? is an essential regulator of epidermal stratification, and is essential for ectodermal development during embryogenesis.

Dataset Information

The protein phosphatase 2A regulatory subunit B55? is a modulator of signaling and microRNA expression in acute myeloid leukemia cells.

Publications

The protein phosphatase 2A regulatory subunit B55α is a modulator of signaling and microRNA expression in acute myeloid leukemia cells.

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