Involvement of MINK, a Ste20 family kinase, in Ras oncogene-induced growth arrest in human ovarian surface epithelial cells.
The ability of activated Ras to induce growth arrest of human ovarian surface epithelial (HOSE) cells via induction of the cyclin-dependent kinase inhibitor p21(WAF1/CIP1) has been used to screen for Ras pathway signaling components using a library of RNA interference (RNAi) vectors targeting the kinome. Two known Ras-regulated kinases were identified, phosphoinositide 3-kinase p110alpha and ribosomal protein S6 kinase p70(S6K1), plus the MAP kinase kinase kinase kinase MINK, which had not previously been implicated in Ras signaling. MINK is activated after Ras induction via a mechanism involving reactive oxygen species and mediates stimulation of the stress-activated protein kinase p38 MAPK downstream of the Raf/ERK pathway. p38 MAPK activation is essential for Ras-induced p21(WAF1/CIP1) upregulation and cell cycle arrest. MINK is thus a distal target of Ras signaling in the induction of a growth-arrested, senescent-like phenotype that may act to oppose oncogenic transformation in HOSE cells.
Nicke
Barbara
B
Signal Transduction Laboratory, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3PX, United Kingdom.
Bastien
Julie
J
Khanna
Sophia J
SJ
Warne
Patricia H
PH
Cowling
Victoria
V
Cook
Simon J
SJ
Peters
Gordon
G
Delpuech
Oona
O
Schulze
Almut
A
Berns
Katrien
K
Mullenders
Jasper
J
Beijersbergen
Roderick L
RL
Bernards
René
R
Ganesan
Trivadi S
TS
Downward
Julian
J
Hancock
David C
DC
D002453:Cell Cycle / Q000502:physiology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004847:Epithelial Cells / Q000201:enzymology*; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D020930:MAP Kinase Kinase Kinases; D010051:Ovarian Neoplasms / Q000201:enzymology*; D010641:Phenotype; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics* / Q000378:metabolism* / Q000494:pharmacology; D034622:RNA Interference / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics; D015398:Signal Transduction / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D050759:Cyclin-Dependent Kinase Inhibitor p21; D047908:Intracellular Signaling Peptides and Proteins; D017382:Reactive Oxygen Species; D029701:Saccharomyces cerevisiae Proteins; C497353:MINK1 protein, human; D017346:Protein Serine-Threonine Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D020930:MAP Kinase Kinase Kinases; C078754:STE20 protein, S cerevisiae; D016283:Proto-Oncogene Proteins p21(ras)