PAK is essential for RAS-induced upregulation of cyclin D1 during the G1 to S transition.
Oncogenic RAS mutants such as v-Ha-RAS induce cell cycling, in particular the G1 to S transition, by upregulating cyclin D1 and downregulating p27, an inhibitor for cyclin-dependent kinases (CDKs). PI-3 kinase appears to be involved in the regulation of both cyclin D1 and p27. In this report, using two distinct inhibitors specific for PAK1-3 (CEP-1347 and WR-PAK18), we present the first evidence indicating that the PIX/Rac/CDC42-dependent Ser/Thr kinases PAK1-3, acting downstream of PI-3 kinase and upstream of the Raf/MEK/ERKs kinase cascade, is essential for RAS-induced upregulation of cyclin D1, but not downregulation of p27. Since these PAK-inhibitors block selectively the malignant growth of RAS transformants, in which PAK1 is constitutively activated, but not normal cell growth, it is suggested that RAS transformants are addicted to the high levels of PAK1 for their malignant entry to S phase.
Nheu
Thao
T
Ludwig Institute for Cancer Research, Parkville/Melbourne, Australia.
He
Hong
H
Hirokawa
Yumiko
Y
Walker
Francesca
F
Wood
John
J
Maruta
Hiroshi
H
D000818:Animals; D002227:Carbazoles / Q000494:pharmacology; D018797:Cell Cycle Proteins / Q000378:metabolism; D019938:Cyclin D1 / Q000378:metabolism*; D015536:Down-Regulation / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016193:G1 Phase / Q000502:physiology; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism; D007211:Indoles / Q000494:pharmacology; D051379:Mice; D008840:Microfilament Proteins / Q000378:metabolism; D009124:Muscle Proteins; D041681:NIH 3T3 Cells; D010455:Peptides / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D064067:Rho Guanine Nucleotide Exchange Factors; D016196:S Phase / Q000502:physiology; D015854:Up-Regulation / Q000502:physiology; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism; D054462:p21-Activated Kinases; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*
D002227:Carbazoles; D018797:Cell Cycle Proteins; D019938:Cyclin D1; D004791:Enzyme Inhibitors; D020662:Guanine Nucleotide Exchange Factors; D007211:Indoles; D008840:Microfilament Proteins; D009124:Muscle Proteins; D010455:Peptides; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D064067:Rho Guanine Nucleotide Exchange Factors; D020764:cdc42 GTP-Binding Protein; D054462:p21-Activated Kinases; D018631:ras Proteins; C058992:Tagln protein, mouse; C487017:WR-PAK18 peptide; C106592:3,9-bis((ethylthio)methyl)-K-252a; C515905:Pak1 protein, mouse; C515909:Pak2 protein, mouse; C515912:Pak3 protein, mouse