PMID- 12821780
OWN - NLM
STAT- MEDLINE
DCOM- 20030904
LR  - 20240214
IS  - 0027-8424 (Print)
IS  - 1091-6490 (Electronic)
IS  - 0027-8424 (Linking)
VI  - 100
IP  - 14
DP  - 2003 Jul 8
TI  - Mdm2-dependent ubiquitination and degradation of the insulin-like growth factor 1 
      receptor.
PG  - 8247-52
AB  - Recently, p53 was demonstrated to affect the expression of the insulin-like 
      growth factor 1 receptor (IGF-1R), a receptor tyrosine kinase that plays a 
      crucial role in growth and survival of cancer cells. However, the underlying 
      mechanisms for interaction between p53 and IGF-1R are still not fully understood. 
      One of the challenging questions remaining to be answered is why the wild-type 
      p53, which per se represses the transcription of the IGF-1R gene, in 
      overexpressed form is necessary for a high IGF-1R expression. In this study, we 
      show that inhibition of p53 causes ubiquitination and down-regulation, through 
      increased degradation, of the IGF-1R in human malignant melanoma cells. This 
      effect, which was independent of the p53 status (i.e., wild type or mutated), was 
      prevented if Mdm2 was coinhibited. Similar results were obtained in UV-irradiated 
      human melanocytes (harboring wild-type p53), in which level of the IGF-1R 
      increased after up-regulation of p53. Interestingly, the basal ubiquitination of 
      the IGF-1R in untreated cells also depended on Mdm2. We could prove that Mdm2 
      physically associates with IGF-1R and that Mdm2 causes IGF-1R ubiquitination in 
      an in vitro assay. Taken together our data provide evidence that Mdm2 serves as a 
      ligase in ubiquitination of the IGF-1R and thereby causes its degradation by the 
      proteasome system. Consequently, by sequestering Mdm2 in the cell nuclei, the 
      level of p53 may indirectly influence the expression of IGF-1R. This role of Mdm2 
      and p53 represents an unexpected mechanism for the regulation of IGF-1R and cell 
      growth.
FAU - Girnita, Leonard
AU  - Girnita L
AD  - Department of Oncology and Pathology, Division of Cellular and Molecular Tumor 
      Pathology, Cancer Center Karolinska, R8:04, Karolinska Hospital, SE-171 76 
      Stockholm, Sweden.
FAU - Girnita, Ada
AU  - Girnita A
FAU - Larsson, Olle
AU  - Larsson O
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20030623
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - 0 (Neoplasm Proteins)
RN  - 0 (Nuclear Proteins)
RN  - 0 (Oligodeoxyribonucleotides, Antisense)
RN  - 0 (Proto-Oncogene Proteins)
RN  - 0 (Recombinant Fusion Proteins)
RN  - 0 (Tumor Suppressor Protein p53)
RN  - 0 (Ubiquitin)
RN  - EC 2.3.2.27 (MDM2 protein, human)
RN  - EC 2.3.2.27 (Mdm2 protein, mouse)
RN  - EC 2.3.2.27 (Proto-Oncogene Proteins c-mdm2)
RN  - EC 2.7.10.1 (Receptor, IGF Type 1)
RN  - EC 3.4.- (Peptide Hydrolases)
RN  - EC 3.4.25.1 (Proteasome Endopeptidase Complex)
RN  - EC 3.4.99.- (ATP dependent 26S protease)
SB  - IM
MH  - 3T3 Cells/metabolism
MH  - Animals
MH  - Cell Nucleus/metabolism
MH  - Down-Regulation/physiology/radiation effects
MH  - Genes, p53
MH  - Humans
MH  - Melanoma/metabolism/pathology
MH  - Mice
MH  - Neoplasm Proteins/antagonists & inhibitors/metabolism
MH  - *Nuclear Proteins
MH  - Oligodeoxyribonucleotides, Antisense/pharmacology
MH  - Peptide Hydrolases/*metabolism
MH  - *Proteasome Endopeptidase Complex
MH  - Protein Interaction Mapping
MH  - Protein Processing, Post-Translational/*physiology
MH  - Proto-Oncogene Proteins/antagonists & inhibitors/*metabolism
MH  - Proto-Oncogene Proteins c-mdm2
MH  - Receptor, IGF Type 1/*metabolism
MH  - Recombinant Fusion Proteins/metabolism
MH  - Transfection
MH  - Tumor Cells, Cultured/metabolism/radiation effects
MH  - Tumor Suppressor Protein p53/antagonists & inhibitors/*metabolism
MH  - Ubiquitin
MH  - Ultraviolet Rays
PMC - PMC166214
EDAT- 2003/06/25 05:00
MHDA- 2003/09/05 05:00
PMCR- 2003/12/23
CRDT- 2003/06/25 05:00
PHST- 2003/06/25 05:00 [pubmed]
PHST- 2003/09/05 05:00 [medline]
PHST- 2003/06/25 05:00 [entrez]
PHST- 2003/12/23 00:00 [pmc-release]
AID - 1431613100 [pii]
AID - 1008247 [pii]
AID - 10.1073/pnas.1431613100 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 2003 Jul 8;100(14):8247-52. doi: 
      10.1073/pnas.1431613100. Epub 2003 Jun 23.