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MDM2 overexpression does not account for stabilization of wild-type p53
protein in non-Hodgkin's lymphomas
R Maestro, A Gloghini, C Doglioni, D Gasparotto, T Vukosavljevic, V De Re, L Laurino, A Carbone and M Boiocchi
Division of Experimental Oncology I, Centro di Riferimento Oncologico,
Aviano, Italy.
p53 protein overexpression is a frequent finding in non-Hodgkin's lymphomas
(NHL), being detected in over 25% of the cases. Moreover, some high-grade
lymphomas and a large fraction of low-grade tumors show a pattern of
scattered p53 accumulation in a limited percentage of neoplastic cells. In
contrast, NHLs show a low frequency of p53 gene mutations. To investigate
the molecular bases of p53 protein overexpression, a large series of NHLs
was analyzed for p53 gene status. The analysis of the entire coding region
of the gene (exons 2- 11) and corresponding donor and acceptor splicing
sites indicated that a significant proportion of p53-positive tumors
overexpresses a wild- type form of p53 protein (wt-p53). To assess whether
wt-p53 accumulation was related to the formation of inactive complexes with
endogenous proteins, MDM2 oncogene expression and amplification were
analyzed. MDM2 overexpression was detected only in one third of the wt-
p53-positive cases, thus excluding that MDM2 accounts tout court for the
accumulation of a normal p53 protein. However, the fact that MDM2
overexpression was detected in only the p53-positive cases and the
observation that MDM2-positive cells were a subpopulation of p53- positive
cells suggest a link between the two phenomena. In particular, our results
indicate that the accumulation of a wt form of p53 protein could promote
the overexpression of the MDM2 gene product. In addition, the prevalence of
MDM2 positivity in intermediate/high-grade tumors together with the
concordant expression of wt-p53 and MDM2 only in the high-grade component
of a 'composite' lymphoma suggests that perturbation in the MDM2/p53
critical ratio could play a role in lymphoma progression.
Volume 85,
Issue 11,
pp. 3239-3246,
06/01/1995
Copyright © 1995 by The American Society of Hematology
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