title: MK3 modulation affects BMI1-dependent and independent cell cycle check-points.
abstract: Although the MK3 gene was originally found deleted in some cancers, it is highly expressed in others. The relevance of MK3 for oncogenesis is currently not clear. We recently reported that MK3 controls ERK activity via a negative feedback mechanism. This prompted us to investigate a potential role for MK3 in cell proliferation. We here show that overexpression of MK3 induces a proliferative arrest in normal diploid human fibroblasts, characterized by enhanced expression of replication stress- and senescence-associated markers. Surprisingly, MK3 depletion evokes similar senescence characteristics in the fibroblast model. We previously identified MK3 as a binding partner of Polycomb Repressive Complex 1 (PRC1) proteins. In the current study we show that MK3 overexpression results in reduced cellular EZH2 levels and concomitant loss of epigenetic H3K27me3-marking and PRC1/chromatin-occupation at the CDKN2A/INK4A locus. In agreement with this, the PRC1 oncoprotein BMI1, but not the PCR2 protein EZH2, bypasses MK3-induced senescence in fibroblasts and suppresses P16INK4A expression. In contrast, BMI1 does not rescue the MK3 loss-of-function phenotype, suggesting the involvement of multiple different checkpoints in gain and loss of MK3 function. Notably, MK3 ablation enhances proliferation in two different cancer cells. Finally, the fibroblast model was used to evaluate the effect of potential tumorigenic MK3 driver-mutations on cell proliferation and M/SAPK signaling imbalance. Taken together, our findings support a role for MK3 in control of proliferation and replicative life-span, in part through concerted action with BMI1, and suggest that the effect of MK3 modulation or mutation on M/SAPK signaling and, ultimately, proliferation, is cell context-dependent.
authors: Department of Molecular Genetics, Maastricht University Medical Centre, Maastricht, the Netherlands.
authors: Peggy
authors: P
authors: Prickaerts
authors: Department of Molecular Genetics, Maastricht University Medical Centre, Maastricht, the Netherlands.
authors: Hanneke E C
authors: HE
authors: Niessen
authors: Department of Molecular Genetics, Maastricht University Medical Centre, Maastricht, the Netherlands.
authors: Vivian E H
authors: VE
authors: Dahlmans
authors: Department of Molecular Genetics, Maastricht University Medical Centre, Maastricht, the Netherlands.
authors: Frank
authors: F
authors: Spaapen
authors: Department of Molecular Genetics, Maastricht University Medical Centre, Maastricht, the Netherlands.
authors: Juliette
authors: J
authors: Salvaing
authors: Department of Molecular Genetics, Maastricht University Medical Centre, Maastricht, the Netherlands.
authors: Jolien
authors: J
authors: Vanhove
authors: Department of Molecular Genetics, Maastricht University Medical Centre, Maastricht, the Netherlands.
authors: Claudia
authors: C
authors: Geijselaers
authors: Department of Molecular Genetics, Maastricht University Medical Centre, Maastricht, the Netherlands.
authors: Stefanie J J
authors: SJ
authors: Bartels
authors: Department of Molecular Genetics, Maastricht University Medical Centre, Maastricht, the Netherlands.
authors: Iris
authors: I
authors: Partouns
authors: Department of Molecular Genetics, Maastricht University Medical Centre, Maastricht, the Netherlands.
authors: Dietbert
authors: D
authors: Neumann
authors: Department of Pathology, Maastricht University Medical Centre, Maastricht, the Netherlands.
authors: Ernst-Jan
authors: EJ
authors: Speel
authors: Department of Stem Cell Biology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan.
authors: Yoshihiro
authors: Y
authors: Takihara
authors: Princess Margaret Cancer Centre and Campbell Family Institute for Cancer Research, Departments of Radiation Oncology and Medical Biophysics, University Health Network, Toronto, Canada, Maastricht Radiation Oncology (MaastRO) Lab, Maastricht University, Maastricht, The Netherlands.
authors: Bradly G
authors: BG
authors: Wouters
authors: Department of Molecular Genetics, Maastricht University Medical Centre, Maastricht, the Netherlands.
authors: Jan Willem
authors: JW
authors: Voncken
mesh_terms: D059447:Cell Cycle Checkpoints; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D016922:Cellular Senescence; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D048054:Mitogen-Activated Protein Kinase 7 / Q000378:metabolism*; D009154:Mutation; D063146:Polycomb-Group Proteins / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D063146:Polycomb-Group Proteins; C098416:MAP-kinase-activated kinase 3; D017346:Protein Serine-Threonine Kinases; C481581:MAPK7 protein, human; D048054:Mitogen-Activated Protein Kinase 7