Perturbations in O-linked beta-N-acetylglucosamine protein modification cause severe defects in mitotic progression and cytokinesis.
The dynamic modification of nuclear and cytoplasmic proteins with O-linked beta-N-acetylglucosamine (O-GlcNAc) is a regulatory post-translational modification that is rapidly responsive to morphogens, hormones, nutrients, and cellular stress. Here we show that O-GlcNAc is an important regulator of the cell cycle. Increased O-GlcNAc (pharmacologically or genetically) results in growth defects linked to delays in G2/M progression, altered mitotic phosphorylation, and cyclin expression. Overexpression of O-GlcNAcase, the enzyme that removes O-GlcNAc, induces a mitotic exit phenotype accompanied by a delay in mitotic phosphorylation, altered cyclin expression, and pronounced disruption in nuclear organization. Overexpression of the O-GlcNAc transferase, the enzyme that adds O-GlcNAc, results in a polyploid phenotype with faulty cytokinesis. Notably, O-GlcNAc transferase is concentrated at the mitotic spindle and midbody at M phase. These data suggest that dynamic O-GlcNAc processing is a pivotal regulatory component of the cell cycle, controlling cell cycle progression by regulating mitotic phosphorylation, cyclin expression, and cell division.
Slawson
Chad
C
Department of Biological Chemistry, the Johns Hopkins School of Medicine, Baltimore, Maryland 21205-2185, USA.
Zachara
Natasha E
NE
Vosseller
Keith
K
Cheung
Win D
WD
Lane
M Daniel
MD
Hart
Gerald W
GW
D041721:3T3-L1 Cells; D000117:Acetylglucosamine / Q000737:chemistry*; D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D015153:Blotting, Western; D002453:Cell Cycle; D002455:Cell Division; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D048749:Cytokinesis; D003593:Cytoplasm / Q000378:metabolism; D005434:Flow Cytometry; D006031:Glycosylation; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D008938:Mitosis; D041681:NIH 3T3 Cells; D010641:Phenotype; D010766:Phosphorylation; D013936:Thymidine / Q000737:chemistry; D013997:Time Factors
D000117:Acetylglucosamine; D013936:Thymidine