Induction of apoptosis by adenovirus E4orf4 protein is specific to transformed cells and requires an interaction with protein phosphatase 2A

Shtrichman, Ronit; Sharf, Rakefet; Barr, Haim; Dobner, Thomas; Kleinberger, Tamar

doi:10.1073/pnas.96.18.10080

Cited by 134 publications

(205 citation statements)

References 36 publications

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“…Even though these viruses are not otherwise related, they all seem to have adapted a similar strategy to affect cellular processes by direct interaction with PP2A. Similar to the Vpr effects, both adenoviral E4orf4 [63][64][65] and HTLV Tax protein induce cell cycle G2 arrest [59]. These two viral proteins both bind to PP2A and affect its enzymatic activity [63,66].…”

Section: Potential Role Of Pp2a In Cell Cycle G2/m Regulation During mentioning

confidence: 99%

Viral infections and cell cycle G2/M regulation

Zhao

Elder

2005

Cell Res

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Progression of cells from G2 phase of the cell cycle to mitosis is a tightly regulated cellular process that requires activation of the Cdc2 kinase, which determines onset of mitosis in all eukaryotic cells. In both human and fission yeast (Schizosaccharomyces pombe) cells, the activity of Cdc2 is regulated in part by the phosphorylation status of tyrosine 15 (Tyr15) on Cdc2, which is phosphorylated by Wee1 kinase during late G2 and is rapidly dephosphorylated by the Cdc25 tyrosine phosphatase to trigger entry into mitosis. These Cdc2 regulators are the downstream targets of two wellcharacterized G2/M checkpoint pathways which prevent cells from entering mitosis when cellular DNA is damaged or when DNA replication is inhibited. Increasing evidence suggests that Cdc2 is also commonly targeted by viral proteins, which modulate host cell cycle machinery to benefit viral survival or replication. In this review, we describe the effect of viral protein R (Vpr) encoded by human immunodeficiency virus type 1 (HIV-1) on cell cycle G2/M regulation. Based on our current knowledge about this viral effect, we hypothesize that Vpr induces cell cycle G2 arrest through a mechanism that is to some extent different from the classic G2/M checkpoints. One the unique features distinguishing Vpr-induced G2 arrest from the classic checkpoints is the role of phosphatase 2A (PP2A) in Vpr-induced G2 arrest. Interestingly, PP2A is targeted by a number of other viral proteins including SV40 small T antigen, polyomavirus T antigen, HTLV Tax and adenovirus E4orf4. Thus an in-depth understanding of the molecular mechanisms underlying Vpr-induced G2 arrest will provide additional insights into the basic biology of cell cycle G2/M regulation and into the biological significance of this effect during host-pathogen interactions.

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Section: Potential Role Of Pp2a In Cell Cycle G2/m Regulation During mentioning

confidence: 99%

Viral infections and cell cycle G2/M regulation

Zhao

Elder

2005

Cell Res

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“…Another viral protein that interacts with PP2A is adenovirus E4orf4. By binding the B subunit in the holoenzyme, E4orf4 induces p53-independent apoptosis (Kleinberger and Shenk, 1993;Marcellus et al, 2000;Shtrichman et al, 1999Shtrichman et al, , 2000. PP2A also associates with numerous cellular proteins that are involved in growth regulation Virshup, 2000).…”

Section: Introductionmentioning

confidence: 99%

Alterations in protein phosphatase 2A subunit interaction in human carcinomas of the lung and colon with mutations in the Aβ subunit gene

2001

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Protein phosphatase 2A (PP2A) consists of three subunits, A, B and C. The A and B subunits have regulatory functions while C is the catalytic subunit. PP2A core enzyme is composed of subunits A and C, and the holoenzyme of subunits A, B and C. All subunits exist as multiple isoforms or splice variants. The A subunit exists as two isoforms, Aa and Ab. Here we report about the properties of eight Ab mutants, which were found in human lung and colon cancer. These mutants were reconstructed by site-directed mutagenesis and assayed for their ability to bind B and C subunits. Two mutants showed decreased binding of PR72, a member of the B'' family of B subunits, but normal C subunit binding; two mutants exhibited decreased binding of the C subunit and of B''/PR72; and one mutant showed increased binding of both the C subunit and B''/PR72. Of three mutants that behaved like the wildtype Ab subunit, one is a polymorphic variant and another one is altered outside the binding region for B and C subunits. Importantly, we also found that the wildtype Aa and Ab isoforms, although 85% identical, are remarkably di erent in their ability to bind B and C subunits. Our ®ndings may have important implications in regard to the role of PP2A as a tumor suppressor.

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“…It down-regulates expression of genes that have been activated by E1A and cAMP (16,17), induces hypophosphorylation of various viral and cellular proteins (16,18), regulates alternative splicing of adenovirus mRNAs (18), and induces p53-independent apoptosis in transformed cells (19 -21). E4orf4-induced apoptosis is specific to transformed cells (22), and thus E4orf4 may have a therapeutic potential for cancer.…”

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confidence: 99%

“…We, and others, have recently shown that the interaction with PP2A complexes that include the B␣/B55, but not the BЈ/B56 subunit, is required for induction of apoptosis by E4orf4 (22)(23)(24). Binding the B subunit alone is not sufficient for induction of apoptosis, because an E4orf4 mutant, A3 (S95P), could bind the B subunit, whereas the A and C subunits were excluded from the complex, causing A3 to act as a dominant negative mutant (23).…”

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confidence: 99%

The Scaffolding A/Tpd3 Subunit and High Phosphatase Activity Are Dispensable for Cdc55 Function in the Saccharomyces cerevisiae Spindle Checkpoint and in Cytokinesis

Koren¹,

Rainis²,

Kleinberger

2004

Journal of Biological Chemistry

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Protein serine/threonine phosphatase 2A (PP2A) is a multifunctional enzyme whose trimeric form consists of a scaffolding A subunit, a catalytic C subunit, and one of several regulatory B subunits (B, B , and B؆). The adenovirus E4orf4 protein associates with PP2A by directly binding the B or B subunits. An interaction with an active PP2A containing the B subunit, or its homologue in yeast, Cdc55, is required for E4orf4-induced apoptosis in mammalian cells and for induction of growth arrest in Saccharomyces cerevisiae. In this work, Cdc55 was randomly mutagenized by low-fidelity PCR amplification, and Cdc55 mutants that lost the ability to transduce the E4orf4 toxic signal in yeast were selected. The mutations obtained by this protocol inhibited the association of Cdc55 with E4orf4, or with the PP2A-AC subunits, or both. Functional analysis revealed that a mutant that does not bind Tpd3, the yeast A subunit, as well as wild type Cdc55 in a tpd3⌬ background, can form a heterodimer with the catalytic subunit. This association requires C subunit carboxyl methylation. The residual phosphatase activity associated with Cdc55 in the absence of Tpd3 is sufficient to maintain a partially active spindle checkpoint and to prevent cytokinesis defects.PP2A 1 is one of the major protein serine/threonine phosphatases in the cell, which plays a role in several cellular processes, including metabolism, transcription, RNA splicing, translation, cell cycle progression, morphogenesis, signal transduction, development, and transformation (1, 2).Several reports indicate that the predominant form of PP2A in cells is a heterotrimer consisting of three subunits. Two of them, the 36-kDa catalytic C subunit and the 63-kDa scaffolding A subunit (PR65), form the core enzyme, and the regulatory B subunit binds the core enzyme to form the holoenzyme. The A and C subunits both exist as two isoforms (␣ and ␤), which are closely related, whereas the B subunit is variable, and its multiple isoforms belong to at least three unrelated gene families, B/B55/PR55 (␣-␦ isoforms), BЈ/B56/PR61 (␣-⑀ isoforms), and BЉ/PR72/PR130/PR59/PR48 (3). The core PP2A enzyme has also been shown to bind other cellular proteins, including striatin and SG2NA (4). Viral proteins, such as the SV40 small t antigen and the polyomavirus small and middle T antigens, can replace the cellular B subunits (5). The various cellular PP2A B subunits target the PP2A holoenzyme to different substrates and dictate its subcellular localization (reviewed in Ref.3).In Saccharomyces cerevisiae, two closely related genes, PPH21 and PPH22, redundantly encode the major PP2A catalytic subunit (6). TPD3 encodes the only A subunit, and two distinct B subunits, encoded by CDC55 and RTS1, are highly homologous to mammalian B and BЈ, respectively (7-9). Mutations of CDC55 are viable, but yield defects in cytokinesis and in the spindle checkpoint and result in abnormal cell morphology. Methylation of the C-terminal leucine residue of the PP2A catalytic subunit by a specific methyltransferase increase...

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Induction of apoptosis by adenovirus E4orf4 protein is specific to transformed cells and requires an interaction with protein phosphatase 2A

Cited by 134 publications

References 36 publications

Viral infections and cell cycle G2/M regulation

Viral infections and cell cycle G2/M regulation

Alterations in protein phosphatase 2A subunit interaction in human carcinomas of the lung and colon with mutations in the Aβ subunit gene

The Scaffolding A/Tpd3 Subunit and High Phosphatase Activity Are Dispensable for Cdc55 Function in the Saccharomyces cerevisiae Spindle Checkpoint and in Cytokinesis

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