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Blood, Vol. 95 No. 12 (June 15), 2000:
pp. 3939-3944
p53 stabilization and functional impairment in the absence of
genetic mutation or the alteration of the
p14ARF-MDM2 loop in ex vivo and cultured
adult T-cell leukemia/lymphoma cells
Shigeki Takemoto,
Raffaella Trovato,
Anna Cereseto,
Christophe Nicot,
Tatiana Kislyakova,
Luca Casareto,
Thomas Waldmann,
Giuseppe Torelli, and
Genoveffa Franchini
From the Basic Research Laboratory, Division of Basic Sciences, and
the Metabolism Branch, Division of Clinical Sciences, National Cancer
Institute, National Institutes of Health, Bethesda, MD; and the Center
Ematologia Sperimentale, University of Modena, Modena, Italy.
Human T-cell lymphotropic virus type I (HTLV-I) transforms T cells
in vitro, and the viral transactivator Tax functionally impairs the
tumor suppressor p53 protein, which is also stabilized in
HTLV-I-infected T cells. Thus, the functional impairment of p53 is
essential to maintain the viral-induced proliferation of CD4+ mature
T cells. However, in the CD4+ leukemic cells of patients with adult
T-cell leukemia/lymphoma (ATLL), the viral transactivator does not
appear to be expressed, and p53 mutations have been found only in a
fraction of patients. We sought to investigate whether p53 function is
impaired, in ex vivo samples from patients with ATLL, in the absence of
genetic mutations. Here we demonstrate that the p53 protein is
stabilized also in ex vivo ATLL samples (10 of 10 studied) and that at
least in 2 patients p53 stabilization was not associated with genetic
mutation. Furthermore, the assessment of p53 function after ionizing
radiation of ATLL cells indicated an abnormal induction of the
p53-responsive genes GADD45 and p21WAF1 in 7 of 7 patients. In 2 of 2 patients, p53 regulation of cell-cycle progression
appeared to be impaired as well. Because p53 is part of a regulatory
loop that also involves MDM2 and p14ARF, the status of the
latter proteins was also assessed in cultured or fresh ATLL cells. The
p97 MDM2 protein was not detected by Western blot analysis in
established HTLV-I-infected T-cell lines or ex vivo ATLL cell lysates.
However, the MDM2 protein could be easily detected after treatment of
cells with the specific proteasome inhibitor lactacystin, suggesting a
normal regulation of the p53-MDM2 regulating loop. Similarly,
p14ARF did not appear to be aberrantly expressed in ex vivo
ATLL cells nor in any of the established HTLV-I-infected T-cell lines
studied. Thus, p53 stabilization in HTLV-I infection occurs in the
absence of genetic mutation and alteration of the physiologic
degradation pathway of p53.
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