Hdm2 nuclear export, regulated by insulin-like growth factor-I/MAPK/p90Rsk signaling, mediates the transformation of human cells

Mark W. Jackson, Linnea E. Patt, Gretchen A. LaRusch, David B. Donner, George R. Stark, Lindsey Mayo

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)16814-16820
Number of pages7
JournalJournal of Biological Chemistry
Volume281
Issue number24
DOIs
StatePublished - Jun 16 2006
Externally publishedYes

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Cell Nucleus Active Transport
Insulin-Like Growth Factor I
Phosphotransferases
Cells
Phosphatidylinositol 3-Kinase
IGF Type 1 Receptor
Oncogene Proteins
Mitogen-Activated Protein Kinase Kinases
p38 Mitogen-Activated Protein Kinases
Fibroblasts
Cell Cycle Checkpoints
Telecommunication links
Cell Survival
Proteins
Chemical activation
Modulation
Pharmacology
Growth

ASJC Scopus subject areas

  • Biochemistry

Cite this

Hdm2 nuclear export, regulated by insulin-like growth factor-I/MAPK/p90Rsk signaling, mediates the transformation of human cells. / Jackson, Mark W.; Patt, Linnea E.; LaRusch, Gretchen A.; Donner, David B.; Stark, George R.; Mayo, Lindsey.

In: Journal of Biological Chemistry, Vol. 281, No. 24, 16.06.2006, p. 16814-16820.

Research output: Contribution to journalArticle

Jackson, Mark W. ; Patt, Linnea E. ; LaRusch, Gretchen A. ; Donner, David B. ; Stark, George R. ; Mayo, Lindsey. / Hdm2 nuclear export, regulated by insulin-like growth factor-I/MAPK/p90Rsk signaling, mediates the transformation of human cells. In: Journal of Biological Chemistry. 2006 ; Vol. 281, No. 24. pp. 16814-16820.
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