The Ink4a tumor suppressor gene product, p19(Arf), interacts with MDM2 and neutralizes MDM2's inhibition of p53 Journal Article

  


Authors: Pomerantz, J.; Schreiber-Agus, N.; Liégeois, N. J.; Silverman, A.; Alland, L.; Chin, L.; Potes, J.; Chen, K.; Orlow, I.; Lee, H. W.; Cordon-Cardo, C.; DePinho, R. A.
Article Title: The Ink4a tumor suppressor gene product, p19(Arf), interacts with MDM2 and neutralizes MDM2's inhibition of p53
Abstract: The INK4a gene encodes two distinct growth inhibitors - the cyclin- dependent kinase inhibitor p16(Ink4a), which is a component of the Rb pathway, and the tumor suppressor p19(Arf), which has been functionally linked to p53. Here we show that p19(Arf) potently suppresses oncogenic transformation in primary cells and that this function is abrogated when p53 is neutralized by viral oncoproteins and dominant-negative mutants but not by the p53 antagonist MDM2. This finding, coupled with the observations that p19(Arf) and MDM2 physically interact and that p19(Arf) blocks MDM2-induced p53 degradation and transactivational silencing, suggests that p19(Arf) functions mechanistically to prevent MDM2's neutralization of p53. Together, our findings ascribe INK4a's potent tumor suppressor activity to the cooperative actions of its two protein products and their relation to the two central growth control pathways, Rb and p53.
Keywords: protein expression; proto-oncogene proteins; proteins; animals; mice; apoptosis; neoplasm proteins; cell line; protein p53; carcinogenesis; nuclear proteins; tumor suppressor gene; tumor suppressor protein p53; gene control; tumor suppressor protein p14arf; lens, crystalline; cyclin dependent kinase inhibitor; retinoblastoma protein; osteoblasts; proto-oncogene proteins c-mdm2; protein dna interaction; staining and labeling; biotin; growth inhibition; dna fragmentation; transformation, genetic; genes, p16; cancer; human; priority journal; article; deoxyuracil nucleotides
Journal Title: Cell
Volume: 92
Issue: 6
ISSN: 0092-8674
Publisher: Cell Press  
Date Published: 1998-03-20
Start Page: 713
End Page: 723
Language: English
DOI: 10.1016/s0092-8674(00)81400-2
PUBMED: 9529248
PROVIDER: scopus
DOI/URL:

https://www.scopus.com/inward/record.uri?eid=2-s2.0-0032549704&doi=10.1016%2fS0092-8674%2800%2981400-2&partnerID=40&md5=edbcdf6c241d59d7614c1c7dfb7c8424
Notes: Article -- Export Date: 12 December 2016 -- Source: Scopus
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MSK Authors
  1. Carlos Cordon-Cardo
    612 Cordon-Cardo
  2. Irene Orlow
    247 Orlow
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