title: Functional and molecular interactions between ERK and CHK2 in diffuse large B-cell lymphoma.
abstract: Distinct oncogenic signalling cascades have been associated with non-Hodgkin lymphoma. ERK1/2 signalling elicits both transcriptional and post-transcriptional effects through phosphorylation of numerous substrates. Here we report a novel molecular relationship between ERK1/2 and CHK2, a protein kinase that is a key mediator of the DNA damage checkpoint that responds to DNA double-strand breaks. Our studies are the first to demonstrate the co-localization and overexpression of ERK1/2 and CHK2 in diffuse large B-cell lymphoma (DLBCL). The physical interaction between ERK and CHK2 was highly dependent on phosphorylated Thr 68 of CHK2. Concurrent administration of an ERK inhibitor enhances the antitumour activity of CHK2 inhibition in both a human DLBCL xenograft model as well as primary human DLBCL cells. Our data suggest a functional interaction between ERK and CHK2 and support the potential combined therapeutic targeting of ERK and CHK2 in human DLBCL.
authors.affiliation: University of Maryland, Marlene & Stewart Greenebaum Cancer Center, Department of Medicine, Baltimore, Maryland 21201, USA.
authors.forename: Bojie
authors.initials: B
authors.lastname: Dai
authors.forename: X Frank
authors.initials: XF
authors.lastname: Zhao
authors.forename: Krystyna
authors.initials: K
authors.lastname: Mazan-Mamczarz
authors.forename: Patrick
authors.initials: P
authors.lastname: Hagner
authors.forename: Sharon
authors.initials: S
authors.lastname: Corl
authors.forename: El Mustapha
authors.initials: el M
authors.lastname: Bahassi
authors.forename: Song
authors.initials: S
authors.lastname: Lu
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Stambrook
authors.forename: Paul
authors.initials: P
authors.lastname: Shapiro
authors.forename: Ronald B
authors.initials: RB
authors.lastname: Gartenhaus
mesh_terms: D017209:Apoptosis / Q000502:physiology; D045744:Cell Line, Tumor; D064447:Checkpoint Kinase 2; D005982:Glutathione Transferase; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D016403:Lymphoma, Large B-Cell, Diffuse / Q000378:metabolism*; D046228:Microarray Analysis; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D005982:Glutathione Transferase; D064447:Checkpoint Kinase 2; C578634:CHEK2 protein, human; D017346:Protein Serine-Threonine Kinases; D048052:Mitogen-Activated Protein Kinase 3