Complex formation of p65/RelA with nuclear Akt1 for enhanced transcriptional activation of NF-kappaB.
Akt1 was revealed to interact with Ki-Ras in the cytoplasm of Ki-Ras-transformed human prostate epithelial cells, 267B1/K-ras. Moreover, p65/RelA in the nucleus was found to interact with both Ki-Ras and Akt1, suggesting the nuclear translocation of Akt1:Ki-Ras complex for NF- kappaB activation. In support of this, compared with wild type Akt1, the dominant negative Akt1 mutant was decreased in its nuclear expression, reducing the Ki-Ras-induced NF-kappaB transcriptional activation. Moreover, inhibitors of Ras (sulindac sulfide and farnesyltransferase inhibitor I) or PI3K/Akt (wortmannin), reduced the amounts of Akt1 and Ki-Ras in the nucleus as well as partial NF-kappaB activity. The complete inhibition of Ki-Ras-induced NF-kappaB activation, however, could only be obtained by combined treatment with wortmannin and proteasome inhibitor-1. Accordingly, clonogenic assay showed Akt1 contribution to IkappaBalpha-mediated NF-kappaB activation for oncogenic cell growth by Ki-Ras. Our data suggest a crucial role of Ki-Ras:Akt1 complex in NF-kappaB transcriptional activation and enhancement of cell survival.
Kwon
Osong
O
Functional Metabolomics Research Center, KRIBB, Yuseong, Daejeon, Republic of Korea.
Kim
Kyung A
KA
He
Long
L
Jung
Mira
M
Jeong
Sook Jung
SJ
Ahn
Jong Seog
JS
Kim
Bo Yeon
BY
D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism*; D004847:Epithelial Cells / Q000378:metabolism*; D006801:Humans; D008297:Male; D046912:Multiprotein Complexes / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D011467:Prostate / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D051996:Transcription Factor RelA / Q000378:metabolism*; D015533:Transcriptional Activation / Q000502:physiology*
D046912:Multiprotein Complexes; D016328:NF-kappa B; C498143:RELA protein, human; D051996:Transcription Factor RelA; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt