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A fostriecin sensitive protein phosphatase, serine/threonine protein phosphatase 4 (PP4) is required for faithful chromosome segregation and mitotic progression into anaphase
Author(s) -
Honkanen Richard,
Theobald Benjamin,
Bonness Kathy
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.839.4
Subject(s) - anaphase , protein phosphatase 2 , mitosis , metaphase , phosphatase , cytokinesis , biology , phosphorylation , microbiology and biotechnology , chemistry , cell cycle , apoptosis , biochemistry , cell division , chromosome , cell , gene
Fostriecin is a phosphate monoester produced by Streptromyces that displays antitumor activity. Fostriecin inhibits the catalytic activity of PPP‐family ser/thr phosphatases (PP1, PP2A, PP4 and PP5), acting as a strong inhibitor of PP2A/PP4 and a weak inhibitor of PP1/PP5. Still, the molecular mechanisms linking phosphatase inhibition and antitumor activity are not clear. The studies reported here reveal that prior to the onset of apoptosis fostriecin disrupts of the metaphase alignment of chromosomes, which produces a prolonged mitotic arrest. To explore the contribution of individual fostriecin‐sensitive phosphatases, antisense‐oligonucleotides that potently and specifically suppress the expression of fostriecin sensitive phosphatases were developed. The suppression of either PP2Aα or PP4, but not PP5 or PP1γ1, was sufficient to induce metaphase arrest, during which time condensed chromosomes fail to achieve normal metaphase alignment. The suppression of PP4 alone induced a strong apoptotic response. Prior to apoptosis, cells with low levels of PP4 arrest in mitosis. In cells with suppressed levels of PP4 that do not become apoptotic, 4N cells that escape mitotic arrest and proceed into an aberrant form of cytokinesis that ultimately fails due to cleavage furrow regression. These studies provide novel evidence that PP4 plays a critical role in the regulation of metaphase progression into anaphase.