Merlin neutralizes the inhibitory effect of Mdm2 on p53.
The stability of p53 tumor suppressor is regulated by Mdm2 via the ubiquitination and proteasome-mediated proteolysis pathway. The c-Abl and PTEN tumor suppressors are known to stabilize p53 by blocking the Mdm2-mediated p53 degradation. This study investigated the correlation between p53 and merlin, a neurofibromatosis 2 (NF2)-related tumor suppressor, in association with the Mdm2 function. The results showed that merlin increased the p53 stability by inhibiting the Mdm2-mediated degradation of p53, which accompanied the increase in the p53-dependent transcriptional activity. The stabilization of p53 by merlin appeared to be accomplished through Mdm2 degradation, and the N-terminal region of merlin was responsible for this novel activity. This study also showed that overexpression of merlin-induced apoptosis of cells depending preferentially on p53 in response to the serum starvation or a chemotherapeutic agent. These results suggest that merlin could be a positive regulator of p53 in terms of tumor suppressor activity, and provide the promising therapeutic means for treating tumors with non-functional merlin or Mdm2 overexpression.
Kim
Hongtae
H
Neuroscience Genome Research Center, The Catholic University of Korea, 505 Banpo-dong, Socho-gu, Seoul 137-701, Korea.
Kwak
Noh-Jin
NJ
Lee
Joo Yong
JY
Choi
Byung Hyune
BH
Lim
Young
Y
Ko
Young Jin
YJ
Kim
Young-Hoon
YH
Huh
Pil-Woo
PW
Lee
Kweon-Haeng
KH
Rha
Hyoung Kyun
HK
Wang
Young-Pil
YP
D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D002455:Cell Division; D053938:DNA Fragmentation; D004268:DNA-Binding Proteins; D004355:Drug Stability; D015870:Gene Expression; D005910:Glioma; D006801:Humans; D008175:Lung Neoplasms; D008579:Meningioma; D051379:Mice; D041681:NIH 3T3 Cells; D025581:Neurofibromin 2 / Q000235:genetics / Q000494:pharmacology* / Q000502:physiology; D009687:Nuclear Proteins; D012516:Osteosarcoma; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000494:pharmacology*; D051736:Proto-Oncogene Proteins c-mdm2; D011993:Recombinant Fusion Proteins; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects; D014162:Transfection; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
D004268:DNA-Binding Proteins; C052130:GAL4 protein, S cerevisiae; D025581:Neurofibromin 2; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D011993:Recombinant Fusion Proteins; D029701:Saccharomyces cerevisiae Proteins; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2