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

The Journal of Biological Chemistry
Mark W JacksonL D Mayo

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.

References

Sep 1, 1984·Proceedings of the National Academy of Sciences of the United States of America·S L HammondM R Stampfer
Sep 30, 1993·International Journal of Cancer. Journal International Du Cancer·K Takahashi, K Suzuki
Sep 23, 1998·Nature·I PalmeroM Serrano
Nov 20, 1998·Molecular and Cellular Biology·D A Freedman, A J Levine
Mar 17, 1999·Proceedings of the National Academy of Sciences of the United States of America·W Tao, A J Levine
Dec 1, 2000·Nature·B VogelsteinA J Levine
Jun 23, 2001·Oncogene·M L AgarwalG R Stark
Aug 16, 2001·Proceedings of the National Academy of Sciences of the United States of America·L D Mayo, D B Donner
Nov 21, 2001·Nature Cell Biology·B P ZhouM C Hung
Mar 6, 2002·The Journal of Biological Chemistry·Lisa Héron-Milhavet, Derek LeRoith
Apr 18, 2002·Oncogene·Margaret AshcroftKaren H Vousden
Jul 12, 2002·The EMBO Journal·Zehavit GoldbergYgal Haupt
Oct 19, 2002·Critical Reviews in Clinical Laboratory Sciences·Paul Shapiro
Nov 27, 2002·Cancer Cell·Yvette R SegerRoberta Maestro
Dec 4, 2002·Journal of Cellular Biochemistry·Susan HauptYgal Haupt
Feb 3, 2005·Oncogene·Hans Oliver WeberKaren H Vousden
Feb 23, 2005·The Journal of Biological Chemistry·Monika PhelpsJeremy P Blaydes
Apr 20, 2005·Oncogene·Sandra L Harris, Arnold J Levine

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Citations

Jan 11, 2013·Nature Reviews. Cancer·Mark WadeGeoffrey M Wahl
Jan 18, 2013·Nature Reviews. Molecular Cell Biology·Astrid Eijkelenboom, Boudewijn M T Burgering
Jan 4, 2008·Molecular and Cellular Biology·Daniele M GilkesJiandong Chen
Dec 4, 2009·The Journal of Clinical Investigation·Shinako ArakiLindsey D Mayo
Nov 10, 2010·The Journal of Clinical Investigation·Cho-Rok JungDong-Soo Im
Jan 11, 2014·Photochemical & Photobiological Sciences : Official Journal of the European Photochemistry Association and the European Society for Photobiology·Anand VenkataramanMark Leid
Sep 10, 2009·Expert Opinion on Drug Discovery·Jason A LehmanLindsey D Mayo
Aug 28, 2014·Journal of Cellular Physiology·Ying-Hua ChengMelissa A Kacena
Dec 11, 2014·Journal of Hematology & Oncology·Patrizia MondelloMichael Mian
Jul 18, 2009·International Journal of Cancer. Journal International Du Cancer·Renyuan ZhouJiaqi Shi
Jan 30, 2013·Biochemical Society Transactions·Emily K RedmanMarcin K Karcz
Sep 14, 2010·Wiley Interdisciplinary Reviews. Systems Biology and Medicine·Gregg L Semenza
Aug 30, 2021·Biochimica Et Biophysica Acta. General Subjects·Aanchal RathiMd Imtaiyaz Hassan

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