The PP2A-Associated Protein α4 Is an Essential Inhibitor of Apoptosis
Abstract
Despite evidence that protein kinases are regulators of apoptosis, a specific role for phosphatases in regulating cell survival has not been established. Here we show that alpha4, a noncatalytic subunit of protein phosphatase 2A (PP2A), is required to repress apoptosis in murine cells. alpha4 is a nonredundant regulator of the dephosphorylation of the transcription factors c-Jun and p53. As a result of alpha4 deletion, multiple proapoptotic genes were transcribed. Either inhibition of new protein synthesis or Bcl-xL overexpression suppressed apoptosis initiated by alpha4 deletion. Thus, mammalian cell viability depends on repression of transcription-initiated apoptosis mediated by a component of PP2A.
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Knockout of Igbp1, encoding alpha4, resulted in embryonic lethality.
“Likewise, knockout of Igbp1, encoding the PP2A biogenesis regulator alpha4 (α4), resulted in embryonic lethality [44].”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [44]
Alpha4-/- MEFs showed increased rates of apoptosis and a 70% reduced activity of immunoprecipitated PP2A-C, decreased levels of A and C subunits, and decreased levels of AC dimers.
“Αlpha4 -/-MEFs showed increased rates of apoptosis and a 70% reduced activity of immunoprecipitated PP2A-C, decreased levels of A and C subunits, and decreased levels of AC dimers.”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [44]
In isolated adipocytes with induced α4 knockout and in vivo upon conditional knockout of α4 in liver, decreased levels of PP2A A and C subunits, decreased PP2A-C methylation, increased H2AX phosphorylation, and induced stress response signals were observed.
“These in vitro biochemical data were further underscored in isolated adipocytes with induced α4 KO [44], as well as in vivo, upon conditional KO of α4 in liver, where, again, decreased levels of PP2A A and C subunits were observed, decreased PP2A-C methylation, increased phosphorylation of H2AX and induced stress response signals [25].”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [44]
All targeted mice died 6 days after induction of hepatic α4 knockout, with livers showing signs of severe apoptosis and increased phosphorylation of p53 and c-jun transcription factors.
“Moreover, all targeted mice died 6 days after induction of hepatic α4 KO, with livers showing signs of severe apoptosis and increased phosphorylation of p53 and c-jun transcription factors [44].”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [44]
Another conditional α4 knockout model confirmed impaired T-cell development, with more immature thymocytes in the thymus and no mature T-cells detectable in peripheral blood.
“The impairment in T-cell development in the absence of α4 was also confirmed in another conditional KO model, where in the thymus more immature thymocytes were observed and no mature T-cells could be detected in peripheral blood [44].”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [44]
In Igbp1 -/- MEFs, reversal of stress-induced phosphorylations is decreased.
“-In -/-MEFs: increased basal phosphorylation of several established | PP2A substrates; decreased reversal of stress-induced | phosphorylations”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [44]
In Igbp1 -/- mice, T-cell development is impaired.
“-Impaired T-cell development [25,44,45]”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [44]
In Bcl-xL-expressing Igbp1 -/- MEFs, cell spreading is slower.
“-In Bcl-x L -expressing MEFs: slower cell spreading; decreased cell | adhesion; reduced cell migration; reduced Rac1 activation; | phenotypes rescued by active Rac1 V12 mutant”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [44]
In Igbp1 -/- MEFs, apoptosis occurs, accompanied by activation of c-jun, p53 and caspase-3 and by PARP cleavage.
“-In -/-MEFs: apoptosis (c-jun, p53 and caspase-3 activation, PARP | cleavage); (partially) rescued by expression of papilloma E6 protein, | or Bcl-xL”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [44]
In Igbp1 -/- liver, there were signs of apoptosis together with p53 and c-Jun activation.
“-In liver: all mice died 6 days after adeno-Cre injection; livers showed | signs of apoptosis and p53 and c-Jun activation”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [44]
In Igbp1 -/- MEFs, several known PP2A substrates show higher basal phosphorylation.
“-In -/-MEFs: increased basal phosphorylation of several established | PP2A substrates; decreased reversal of stress-induced | phosphorylations”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [44]
In Igbp1 -/- liver, every mouse died six days after adeno-Cre injection.
“-In liver: all mice died 6 days after adeno-Cre injection; livers showed | signs of apoptosis and p53 and c-Jun activation”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [44]
In these cells, cell adhesion is decreased.
“-In Bcl-x L -expressing MEFs: slower cell spreading; decreased cell | adhesion; reduced cell migration; reduced Rac1 activation; | phenotypes rescued by active Rac1 V12 mutant”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [44]
In these cells, cell migration is reduced.
“-In Bcl-x L -expressing MEFs: slower cell spreading; decreased cell | adhesion; reduced cell migration; reduced Rac1 activation; | phenotypes rescued by active Rac1 V12 mutant”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [44]
In Igbp1 -/- MEFs, apoptosis is partly reversed by papilloma E6 protein or Bcl-xL expression.
“-In -/-MEFs: apoptosis (c-jun, p53 and caspase-3 activation, PARP | cleavage); (partially) rescued by expression of papilloma E6 protein, | or Bcl-xL”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [44]
In Igbp1 -/- adipocytes, apoptosis occurs, with c-jun, p53 and caspase-3 activation.
“-In -/-adipocytes: apoptosis (c-jun, p53, caspase-3 activation)”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [44]
In these cells, Rac1 activation is reduced.
“-In Bcl-x L -expressing MEFs: slower cell spreading; decreased cell | adhesion; reduced cell migration; reduced Rac1 activation; | phenotypes rescued by active Rac1 V12 mutant”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [44]
In these cells, the phenotypes are rescued by active Rac1 V12 mutant.
“-In Bcl-x L -expressing MEFs: slower cell spreading; decreased cell | adhesion; reduced cell migration; reduced Rac1 activation; | phenotypes rescued by active Rac1 V12 mutant”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [44]
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- Authors
- Kong, M., Fox, C. J., Mu, J., Solt, L., Xu, A., Cinalli, R. M., Birnbaum, M. J., Lindsten, T., & Thompson, C. B.
- Affiliations
- Howard Hughes Medical Institute (US)
- Corresponding author
- Thompson, Craig B.
- Venue
- Science
- Published
- 2004-10-22
- Volume
- 306
- Issue
- 5696
- Pages
- 695-698
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- OpenAlex
- W2004361019
- Cited by
- 149
- References
- 22
- Citations by year
- 2026: 2 · 2024: 1 · 2022: 1 · 2021: 5 · 2020: 3 · 2019: 1 · 2018: 4 · 2017: 7 · 2016: 4 · 2015: 5 · 2014: 11 · 2013: 8 · 2012: 14
- FWCI
- 3.32
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- protein phosphatase 2A, apoptosis inhibition, transcriptional repression, Bcl-xL, cell viability
- MeSH terms
- Animals, Cell Differentiation, Cell Line, Cell Survival, Cells, Cultured, Cycloheximide, Liver, Mice, Transgenic, Phosphoprotein Phosphatases, Phosphoproteins, Phosphorylation, Protein Synthesis Inhibitors, Transcription, Genetic, Tumor Suppressor Protein p53, Proto-Oncogene Proteins c-jun, Apoptosis, Gene Deletion, Adipocytes, Molecular Chaperones, Proto-Oncogene Proteins c-bcl-2, Oligonucleotide Array Sequence Analysis, Gene Expression Profiling, Intercellular Signaling Peptides and Proteins, PPAR gamma, Adaptor Proteins, Signal Transducing, bcl-X Protein, Mice, Protein Phosphatase 2
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