Lyn tyrosine kinase inhibits nuclear export of the p53 tumor suppressor.
The p53 tumor suppressor is activated in the cellular response to stress. Mdm2 inhibits p53-dependent transactivation and promotes degradation of p53 by the ubiquitin-proteosome pathway. The present studies demonstrate that p53 binds directly to the nuclear Lyn tyrosine kinase. Lyn increases p53 levels and stimulates p53-mediated transcription by a kinase-independent mechanism. The results also demonstrate that Lyn increases nuclear levels of ubiquitinated p53 by inhibiting export of p53 to the cytoplasm. In concert with these results, Lyn reverses Mdm2-mediated degradation of p53 and increases p53-dependent apoptosis. Our findings support a previously undefined role for nuclear Lyn in both activation and Mdm2-mediated regulation of p53.
Ren
Xinping
X
Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.
Cao
Cheng
C
Zhu
Liben
L
Yoshida
Kiyotsugu
K
Kharbanda
Surender
S
Weichselbaum
Ralph
R
Kufe
Donald
D
D021581:Active Transport, Cell Nucleus; D017209:Apoptosis / Q000187:drug effects; D002467:Cell Nucleus / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D016147:Genes, Tumor Suppressor; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D008156:Luciferases / Q000378:metabolism; D018613:Microscopy, Confocal; D009687:Nuclear Proteins; D010957:Plasmids; D011233:Precipitin Tests; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2; D011993:Recombinant Fusion Proteins / Q000302:isolation & purification / Q000378:metabolism; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured / Q000378:metabolism / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism*
D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D011993:Recombinant Fusion Proteins; D016159:Tumor Suppressor Protein p53; D025801:Ubiquitin; D008156:Luciferases; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D005982:Glutathione Transferase; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases