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From the Molecular Pathology Program,*
Centro Nacionalde Investigaciones Oncológicas (CN10), and the Department ofImmunology and Oncology,
Centro Nacional deBiotechnología/Concejo Superior de InvestigicionasCientíficas-Pharmacia Corporation, Cantoblanco, Madrid, Spain
The development of human cancers is frequently associated with the silencing of the two major tumor suppressor pathways represented by retinoblastoma protein and p53. As the incidence of p53 mutations is significantly lower in Hodgkin’s lymphoma than in other neoplasias, we investigated whether the malfunction of other proteins in this pathway could be responsible for its inactivation. Because the existence of nucleolar complexes between p14ARF and Hdm2 has been described as having a critical effect on p53 function by inhibiting its degradation, we analyzed the expression and subcellular localization of these proteins in 52 cases and in Hodgkin’s cell lines. Two of four cell lines revealed loss of p14ARF expression secondary to gene promoter methylation, this being mutually exclusive with p53 mutations (1 of 4), illustrating the existence of selective pressure to inactivate the p53 pathway. The majority of Hodgkin’s samples showed a strong nucleolar expression of p14ARF that was not associated with Hdm2. They also showed the existence of Hdm2/p53 complexes, and the absence of complexes containing either p14ARF/Hdm2 or p14ARF/p53. The different localization of Hdm2 (nucleoplasm) and p14ARF (nucleoli) observed in Hodgkin’s tumors and cell lines is associated with the presence of short alternatively spliced transcripts of Hdm2 lacking the ARF-binding region and the nuclear export signal. The absence of these p14ARF/Hdm2 nucleolar complexes could be sufficient to inactivate the pathway and may explain the low frequency of p53 mutations in this tumor.
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