title: ERK5/BMK1 is a novel target of the tumor suppressor VHL: implication in clear cell renal carcinoma.
abstract: Extracellular signal-regulated kinase 5 (ERK5), also known as big mitogen-activated protein kinase (MAPK) 1, is implicated in a wide range of biologic processes, which include proliferation or vascularization. Here, we show that ERK5 is degraded through the ubiquitin-proteasome system, in a process mediated by the tumor suppressor von Hippel-Lindau (VHL) gene, through a prolyl hydroxylation-dependent mechanism. Our conclusions derive from transient transfection assays in Cos7 cells, as well as the study of endogenous ERK5 in different experimental systems such as MCF7, HMEC, or Caki-2 cell lines. In fact, the specific knockdown of ERK5 in pVHL-negative cell lines promotes a decrease in proliferation and migration, supporting the role of this MAPK in cellular transformation. Furthermore, in a short series of fresh samples from human clear cell renal cell carcinoma, high levels of ERK5 correlate with more aggressive and metastatic stages of the disease. Therefore, our results provide new biochemical data suggesting that ERK5 is a novel target of the tumor suppressor VHL, opening a new field of research on the role of ERK5 in renal carcinomas.
authors.affiliation: Laboratorio de Oncología Molecular, Centro Regional de Investigaciones Biomédicas/University of Castilla la Mancha CRIB/UCLM, Albacete, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Arias-González
authors.forename: Inmaculada
authors.initials: I
authors.lastname: Moreno-Gimeno
authors.forename: Antonio Rubio
authors.initials: AR
authors.lastname: del Campo
authors.forename: Leticia
authors.initials: L
authors.lastname: Serrano-Oviedo
authors.forename: María Llanos
authors.initials: ML
authors.lastname: Valero
authors.forename: Azucena
authors.initials: A
authors.lastname: Esparís-Ogando
authors.forename: Miguel Ángel
authors.initials: MÁ
authors.lastname: de la Cruz-Morcillo
authors.forename: Pedro
authors.initials: P
authors.lastname: Melgar-Rojas
authors.forename: Jesús
authors.initials: J
authors.lastname: García-Cano
authors.forename: Francisco José
authors.initials: FJ
authors.lastname: Cimas
authors.forename: María José Ruiz
authors.initials: MJ
authors.lastname: Hidalgo
authors.forename: Alfonso
authors.initials: A
authors.lastname: Prado
authors.forename: Juan Luis
authors.initials: JL
authors.lastname: Callejas-Valera
authors.forename: Syong Hyun
authors.initials: SH
authors.lastname: Nam-Cha
authors.forename: José Miguel
authors.initials: JM
authors.lastname: Giménez-Bachs
authors.forename: Antonio S
authors.initials: AS
authors.lastname: Salinas-Sánchez
authors.forename: Atanasio
authors.initials: A
authors.lastname: Pandiella
authors.forename: Luis
authors.initials: L
authors.lastname: del Peso
authors.forename: Ricardo
authors.initials: R
authors.lastname: Sánchez-Prieto
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D001483:Base Sequence; D019556:COS Cells; D002292:Carcinoma, Renal Cell / Q000378:metabolism* / Q000473:pathology; D002460:Cell Line; D002465:Cell Movement; D002522:Chlorocebus aethiops; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D006900:Hydroxylation; D007680:Kidney Neoplasms / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D048054:Mitogen-Activated Protein Kinase 7 / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D011379:Prognosis; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D025801:Ubiquitin; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D048054:Mitogen-Activated Protein Kinase 7; D046988:Proteasome Endopeptidase Complex; C497446:VHL protein, human