Reduced expression of the A? subunit of protein phosphatase 2A in human gliomas in the absence of mutations in the A? and A? subunit genes

Colella, Stefano; Ohgaki, Hideaki; Ruediger, Ralf; Yang, Fan; Nakamura, Mitsutoshi; Fujisawa, Hironori; Kleihues, Paul; Walter, Gernot

doi:10.1002/ijc.1423

Cited by 60 publications

(57 citation statements)

References 34 publications

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“…In apparent contradiction to our study, Collela et al (55) analyzed 58 human brain tumor samples and found that nearly half expressed little or no detectable A␣/␤ subunit protein. Intriguingly, all samples had near normal levels of catalytic and B family regulatory subunits.…”

Section: Discussioncontrasting

confidence: 99%

Critical Role for Protein Phosphatase 2A Heterotrimers in Mammalian Cell Survival

Strack

Cribbs

Gomez

2004

Journal of Biological Chemistry

141

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The predominant forms of protein phosphatase 2A (PP2A), one of the major Ser/Thr phosphatases, are dimers of catalytic (C) and scaffolding (A) subunits and trimers with an additional variable regulatory subunit. In mammals, catalytic and scaffolding subunits are encoded by two genes each (␣/␤), whereas three gene families (B, B , and B؆) with a total of 12 genes contribute PP2A regulatory subunits. We generated stable PC12 cell lines in which the major scaffolding A␣ subunit can be knocked down by inducible RNA interference (RNAi) to study its role in cell viability. A␣ RNAi decreased total PP2A activity as well as protein levels of C, B, and B but not B؆ subunits. Inhibitor experiments indicate that monomeric C and B subunits are degraded by the proteosome. Knock-down of A␣ triggered cell death by redundant apoptotic and non-apoptotic mechanisms because the inhibition of RNAi-associated caspase activation failed to stall cell death. PP2A holoenzymes positively regulate survival kinase signaling, because RNAi reduced basal and epidermal growth factor-stimulated Akt phosphorylation. RNAi-resistant A␣ cDNAs rescued RNAi-induced loss of the C subunit, and A␣ point mutants prevented regulatory subunit degradation as predicted from each mutant's binding specificity. In transient, stable, and stable-inducible rescue experiments, both wild-type A␤ and A␣ mutants capable of binding to at least one family of regulatory subunits were able to delay A␣ RNAi-induced death of PC12 cells. However, only the expression of wild-type A␣ restored viability completely. Thus, heterotrimeric PP2A holoenzymes containing the A␣ subunit and members of all three regulatory subunit families are necessary for mammalian cell viability.

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Section: Discussioncontrasting

confidence: 99%

Critical Role for Protein Phosphatase 2A Heterotrimers in Mammalian Cell Survival

Strack

Cribbs

Gomez

2004

Journal of Biological Chemistry

141

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“…In addition to mutations, alterations in the expression levels of PP2A regulatory subunits are also found in human cancers. Reduction of PP2A Aa expression was found in 43% of primary human gliomas (Colella et al, 2001) and downregulation of B56g was observed in human primary melanoma specimens (Deichmann et al, 2001). In addition, three subunits of the type 2A group of phosphatases, PP4 (PP4C, PP4R2 and PP4R3), are highly expressed in human primary breast and lung tumors .…”

Section: Discussionmentioning

confidence: 99%

α4 is highly expressed in carcinogen-transformed human cells and primary human cancers

et al. 2011

Oncogene

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A regulator of the protein phosphatase 2A (PP2A), a4, has been implicated in a variety of functions that regulate many cellular processes. To explore the role of a4 in human cell transformation and tumorigenesis, we show that a4 is highly expressed in human cells transformed by chemical carcinogens including benzo(a)pyrene, aflatoxin B 1 , N-methyl-N 0 -nitro-N-nitrosoguanidine, nickel sulfate and in several hepatic and lung cancer cell lines. In addition, overexpression of a4 was detected in 87.5% (74/80) of primary hepatocellular carcinomas, 84.0% (21/25) of primary lung cancers and 81.8% (9/11) of primary breast cancers, indicating that a4 is ubiquitously highly expressed in human cancer. Functional studies revealed that elevated a4 expression results in an increase in cell proliferation, promotion of cell survival and decreased PP2A-attributable activity. Importantly, ectopic expression of a4 permits non-transformed human embryonic kidney cells (HEKTER) and L02R cells to form tumors in immunodeficient mice. Furthermore, we show that the highly expressed a4 in transformed cells or human tumors is not regulated by DNA hypomethylation. A microRNA, miR-34b, that suppresses the expression of a4 through specific binding to the 3 0 -untranslated region of a4 is downregulated in transformed or human lung tumors. Taken together, these observations identify that a4 possesses an oncogenic function. Reduction of PP2A activity due to an enhanced a4-PP2A interaction contributes directly to chemical carcinogen-induced tumorigenesis.

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“…Similarly, loss or reduced expression of PR65 has been detected in human gliomas and breast cancer cell lines (Colella et al, 2001;Suzuki and Takahashi, 2003). Accordingly, in immortalised but not tumorigenic cells, expression of PR65/Aa mutants defective in binding to other PP2A subunits partially suppressed endogenous PP2A-Aa expression, activated the AKT pathway and promoted tumour formation in immunodeficient mice (Chen et al, 2005b).…”

Section: Protein Phosphatase 2a (Pp2a) a Phosphatase With Tumour Supmentioning

confidence: 94%

ReSETting PP2A tumour suppressor activity in blast crisis and imatinib-resistant chronic myelogenous leukaemia

Perrotti

Neviani

2006

Br J Cancer

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The deregulated kinase activity of p210-BCR/ABL oncoproteins, hallmark of chronic myelogenous leukaemia (CML), induces and sustains the leukaemic phenotype, and contributes to disease progression. Imatinib mesylate, a BCR/ABL kinase inhibitor, is effective in most of chronic phase CML patients. However, a significant percentage of CML patients develop resistance to imatinib and/or still progresses to blast crisis, a disease stage that is often refractory to imatinib therapy. Furthermore, there is compelling evidence indicating that the CML leukaemia stem cell is also resistant to imatinib. Thus, there is still a need for new drugs that, if combined with imatinib, will decrease the rate of relapse, fully overcome imatinib resistance and prevent blastic transformation of CML. We recently reported that the activity of the tumour suppressor protein phosphatase 2A (PP2A) is markedly inhibited in blast crisis CML patient cells and that molecular or pharmacologic re-activation of PP2A phosphatase led to growth suppression, enhanced apoptosis, impaired clonogenic potential and decreased in vivo leukaemogenesis of imatinib-sensitive and -resistant (T315I included) CML-BC patient cells and/or BCR/ABL þ myeloid progenitor cell lines. Thus, the combination of PP2A phosphatase-activating and BCR/ABL kinase-inhibiting drugs may represent a powerful therapeutic strategy for blast crisis CML patients.

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Reduced expression of the A? subunit of protein phosphatase 2A in human gliomas in the absence of mutations in the A? and A? subunit genes

Cited by 60 publications

References 34 publications

Critical Role for Protein Phosphatase 2A Heterotrimers in Mammalian Cell Survival

Critical Role for Protein Phosphatase 2A Heterotrimers in Mammalian Cell Survival

α4 is highly expressed in carcinogen-transformed human cells and primary human cancers

ReSETting PP2A tumour suppressor activity in blast crisis and imatinib-resistant chronic myelogenous leukaemia

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