Nucleo-cytoplasmic shuttling of the hdm2 oncoprotein regulates the levels of the p53 protein via a pathway used by the human immunodeficiency virus rev protein.
The hdm2 gene is overexpressed in a variety of human tumors. Its gene product localizes predominantly to the nucleus, where it acts as an inhibitor of the p53 tumor suppressor gene product. It is shown here that the hdm2 oncoprotein constantly shuttles between the nucleus and the cytoplasm. Shuttling of hdm2 does not depend on its interaction with p53. Nuclear export of hdm2 is mediated by a signal sequence similar to the nuclear export signal of the rev protein from human immunodeficiency virus and other lentiviruses. Mutation of this signal sequence abolishes detectable nucleo-cytoplasmic shuttling. When fused to a carrier protein, the hdm2 signal sequence can mediate nuclear export after intranuclear microinjection into HeLa cells. The export of hdm2 can be blocked by a competitive inhibitor of rev export, arguing that the export pathways for hdm2 and rev are either overlapping or identical. Inhibition of its export modifies the ability of hdm2 to block p53-mediated transcriptional activation, and hdm2's export function is required to accelerate the degradation of p53. Thus the rev nuclear export pathway may be used to regulate an oncogene product's activity and modulate cellular growth.
Roth
J
J
Department of Molecular Biology, Princeton University, Lewis Thomas Laboratory, NJ 08544-1014, USA.
Dobbelstein
M
M
Freedman
D A
DA
Shenk
T
T
Levine
A J
AJ
D000595:Amino Acid Sequence; D001692:Biological Transport / Q000235:genetics; D002352:Carrier Proteins / Q000378:metabolism; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D003593:Cytoplasm / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D015694:Gene Products, rev / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology; D006367:HeLa Cells; D006801:Humans; D008969:Molecular Sequence Data; D009687:Nuclear Proteins; D021382:Protein Sorting Signals / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D051736:Proto-Oncogene Proteins c-mdm2; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism / Q000502:physiology
D002352:Carrier Proteins; D015694:Gene Products, rev; D009687:Nuclear Proteins; D021382:Protein Sorting Signals; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2