Hdm2 nuclear export, regulated by insulin-like growth factor-I/MAPK/p90Rsk signaling, mediates the transformation of human cells.
Insulin-like growth factor (IGF)-I receptor activation leads to enhanced proliferation and cell survival via the MAP kinase and phosphatidylinositol 3-kinase-signaling pathways. Upon stimulation by IGF-I, the Hdm2 oncoprotein is phosphorylated by AKT, leading to its rapid nuclear translocation and subsequent inhibition of p53. We now show that IGF-I stimulation regulates the nuclear export of Hdm2 and p53 via the MAP kinase pathway. Inhibition of p38 MAPK or MEK via pharmacological means or expression of dominant negative proteins inhibited the cytoplasmic accumulation of Hdm2 and increased Hdm2 and p53 protein levels, whereas constitutively active p90Rsk promoted the nuclear export of Hdm2. Expression of constitutively active p90Rsk with E1A, oncogenic H-Ras, and hTERT resulted in the anchorage-independent growth of normal human fibroblasts. Our findings link p90Rsk-mediated modulation of Hdm2 nuclear to cytoplasmic shuttling with the diminished ability of p53 to regulate cell cycle checkpoints that ultimately leads to transformation.
Jackson
Mark W
MW
Department of Molecular Genetics, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA.
Patt
Linnea E
LE
LaRusch
Gretchen A
GA
Donner
David B
DB
Stark
George R
GR
Mayo
Lindsey D
LD
D021581:Active Transport, Cell Nucleus; D045744:Cell Line, Tumor; D003593:Cytoplasm / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D020935:MAP Kinase Signaling System; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism*; D012190:Retroviridae / Q000235:genetics; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000378:metabolism*; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D016159:Tumor Suppressor Protein p53; D007334:Insulin-Like Growth Factor I; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D019869:Phosphatidylinositol 3-Kinases; D038744:Ribosomal Protein S6 Kinases, 90-kDa