title: RhoA modulates functional and physical interaction between ROCK1 and Erk1/2 in selenite-induced apoptosis of leukaemia cells.
abstract: RhoA GTPase dysregulation is frequently reported in various tumours and haematologic malignancies. RhoA, regulating Rho-associated coiled-coil-forming kinase 1 (ROCK1), modulates multiple cell functions, including malignant transformation, metastasis and cell death. Therefore, RhoA/ROCK1 could be an ideal candidate target in cancer treatment. However, the roles of RhoA/ROCK1 axis in apoptosis of leukaemia cells remain elusive. In this study, we explored the effects of RhoA/ROCK1 cascade on selenite-induced apoptosis of leukaemia cells and the underlying mechanism. We found selenite deactivated RhoA/ROCK1 and decreased the association between RhoA and ROCK1 in leukaemia NB4 and Jurkat cells. The inhibited RhoA/ROCK1 signalling enhanced the phosphorylation of Erk1/2 in a Mek1/2-independent manner. Erk1/2 promoted apoptosis of leukaemia cells after it was activated. Intriguingly, it was shown that both RhoA and ROCK1 were present in the multimolecular complex containing Erk1/2. GST pull-down analysis showed ROCK1 had a direct interaction with GST-Erk2. In addition, selenite-induced apoptosis in an NB4 xenograft model was also found to be associated with the RhoA/ROCK1/Erk1/2 pathway. Our data demonstrate that the RhoA/ROCK1 signalling pathway has important roles in the determination of cell fates and the modulation of Erk1/2 activity at the Mek-Erk interplay level.
authors.affiliation: State Key Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medicine Sciences & School of Basic Medicine, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.
authors.forename: F
authors.initials: F
authors.lastname: Li
authors.forename: Q
authors.initials: Q
authors.lastname: Jiang
authors.forename: K J
authors.initials: KJ
authors.lastname: Shi
authors.forename: H
authors.initials: H
authors.lastname: Luo
authors.forename: Y
authors.initials: Y
authors.lastname: Yang
authors.forename: C M
authors.initials: CM
authors.lastname: Xu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D006801:Humans; D019169:Jurkat Cells; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D008819:Mice, Nude; D058990:Molecular Targeted Therapy; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D020887:Selenious Acid / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays; D054460:rho-Associated Kinases / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000502:physiology*
chemical_list: D000970:Antineoplastic Agents; C066737:RHOA protein, human; C515851:ROCK1 protein, human; D054460:rho-Associated Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; C505407:CASP3 protein, human; C506433:CASP9 protein, human; D053148:Caspase 3; D053453:Caspase 9; D020742:rhoA GTP-Binding Protein; D020887:Selenious Acid