Adenovirus protein E4orf4 induces premature APCCdc20 activation in Saccharomyces cerevisiae by a protein phosphatase 2A-dependent mechanism.
Protein phosphatase 2A (PP2A) has been implicated in cell cycle progression and mitosis; however, the complexity of PP2A regulation via multiple B subunits makes its functional characterization a significant challenge. The human adenovirus protein E4orf4 has been found to induce both high Cdk1 activity and the accumulation of cells in G(2)/M in both mammalian and yeast cells, effects which are largely dependent on the B55/Cdc55 regulatory subunit of PP2A. Thus, E4orf4 represents a unique means by which the function of a specific form of PP2A can be delineated in vivo. In Saccharomyces cerevisiae, only two PP2A regulatory subunits exist, Cdc55 and Rts1. Here, we show that E4orf4-induced toxicity depends on a functional interaction with Cdc55. E4orf4 expression correlates with the inappropriate reduction of Pds1 and Scc1 in S-phase-arrested cells. The unscheduled loss of these proteins suggests the involvement of PP2A(Cdc55) in the regulation of the Cdc20 form of the anaphase-promoting complex (APC). Contrastingly, activity of the Hct1 form of the APC is not induced by E4orf4, as demonstrated by the observed stability of its substrates. We propose that E4orf4, being a Cdc55-specific inhibitor of PP2A, demonstrates the role of PP2A(Cdc55) in regulating APC(Cdc20) activity.
Mui
Melissa Z
MZ
Department of Biochemistry, the Goodman Cancer Centre, McGill University, McIntyre Medical Building, Room 822, 3655 Promenade Sir William Osler, Montreal, Quebec H3G 1Y6, Canada.
Roopchand
Diana E
DE
Gentry
Matthew S
MS
Hallberg
Richard L
RL
Vogel
Jackie
J
Branton
Philip E
PE
D000260:Adenoviruses, Human / Q000235:genetics*; D064173:Anaphase-Promoting Complex-Cyclosome; D064199:Cdc20 Proteins; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism; D015966:Gene Expression Regulation, Fungal; D006801:Humans; D009687:Nuclear Proteins / Q000378:metabolism; D011485:Protein Binding; D025941:Protein Interaction Mapping; D054648:Protein Phosphatase 2 / Q000235:genetics / Q000378:metabolism*; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism*; D064249:Securin; D043743:Ubiquitin-Protein Ligase Complexes / Q000378:metabolism*; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism*
C577495:CDC20 protein, S cerevisiae; C071246:CDC55 protein, S cerevisiae; D064199:Cdc20 Proteins; D018797:Cell Cycle Proteins; D002868:Chromosomal Proteins, Non-Histone; C121517:E4orf4 protein, adenovirus; C490529:MCD1 protein, S cerevisiae; D009687:Nuclear Proteins; C578004:PDS1 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D064249:Securin; D014764:Viral Proteins; D043743:Ubiquitin-Protein Ligase Complexes; D064173:Anaphase-Promoting Complex-Cyclosome; D054648:Protein Phosphatase 2