HOX11 interacts with protein phosphatases PP2A and PP1 and disrupts a G2/M cell-cycle checkpoint.
Hox11 is an orphan homeobox gene that controls the genesis of the spleen. HOX11 is also oncogenic, having been isolated from a chromosomal breakpoint in human T-cell leukaemia. Transgenic mice that redirected HOX11 to the thymus demonstrated cell-cycle aberration and progression to malignancy. We observed that the protein HOX11 interacted with protein serine-threonine phosphatase 2A catalytic subunit (PP2AC), as well as protein phosphatase 1 (PP1C) in mammalian cells. Inhibition of PP2A can regulate the cell cycle and control the activation of maturation-promoting factor in Xenopus oocytes. Microinjection of HOX11 into Xenopus oocytes arrested at the G2 phase of the cell cycle promoted progression to the M phase. G2 arrest can be induced by gamma-irradiation, but is eliminated by expression of HOX11 within a T-cell line. Thus HOX11 is a cellular oncogene that targets PP2A and PP1, both of which are targets for oncogenic viruses and chemical tumour promoters. This interaction suggests a mechanism by which a homeobox can alter the cell cycle.
Kawabe
T
T
Howard Hughes Medical Institute, Washington University School of Medicine, St Louis, Missouri 63110, USA.
Muslin
A J
AJ
Korsmeyer
S J
SJ
D000818:Animals; D001665:Binding Sites; D002453:Cell Cycle / Q000502:physiology / Q000528:radiation effects; D016195:G2 Phase / Q000502:physiology*; D005720:Gamma Rays; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D019169:Jurkat Cells; D051379:Mice; D008938:Mitosis / Q000502:physiology*; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D009865:Oocytes; D010749:Phosphoprotein Phosphatases / Q000378:metabolism*; D011485:Protein Binding; D054645:Protein Phosphatase 1; D054648:Protein Phosphatase 2; D011518:Proto-Oncogene Proteins; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D013601:T-Lymphocytes / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014981:Xenopus; D029867:Xenopus Proteins
D018398:Homeodomain Proteins; D015513:Oncogene Proteins; D011518:Proto-Oncogene Proteins; D011993:Recombinant Fusion Proteins; C487378:Tlx1 protein, mouse; D029867:Xenopus Proteins; C489501:tlx1 protein, Xenopus; C071250:TLX1 protein, human; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1; D054648:Protein Phosphatase 2