ERK promotes tumorigenesis by inhibiting FOXO3a via MDM2-mediated degradation

Nature Cell Biology 10, 138 - 148 (2008)

Speaker: Yu-Ting Kao (高毓婷)               Time: 14:00~15:00, Apr. 30, 2008

Commentator: 呂佩融老師                 Place: Room 601

Abstract:

   FORKHEAD BOX O3a (FOXO3a) is one of the FOXO family members. All the seven members of FOXO transcription factors activate or repress multiple target genes, such as Bim and FasL involved in apoptosis; p27^KIP1 and p21^WAF1 involved in cell cycle regulation. Multiple signaling pathways may regulate FOXO activity. PKB/Akt phosphorylates FOXO3a, and alters the transcription activity, cellular localization and degradation of FOXO3a. ERK and p38 were shown to phosphorylate FOXO1 (function similar to FOXO3a) at various sites, suggesting that the RAS-MAPK signaling pathway may play an important role in FOXO regulation. In this seminar paper, the authors unravel that ERK suppressed FOXO3a stability, transcription activity and induced nuclear exclusion of FOXO3a. ERK interacted with and phosphorylated FOXO3a at Ser 294, Ser 344, and Ser 425. MDM2, up-regulated by Ras-driven Raf/MEK/MAP kinase pathway, was required for ERK-mediated FOXO3a degradation via the ubiquitin-proteasome pathway. Finally, the authors proved that inhibition of ERK-mediated posphorylation on FOXO3a could inhibit tumorigenesis and induced apoptosis. In conclusion, this study reveal a novel pathway in cell growth and tumorigenesis through negative regulation of FOXO3a by RAS-ERK pathway and MDM2. Since cancer cells acquire resistance to apoptosis and become out of growth control; it is possible to increase the therapeutic efficacy of ERK inhibitors by concurrent activation of FOXO3a.

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