Analysis of the molecular species generated by MDM2 gene amplification in liposarcomas.
MDM2 gene is overexpressed in several tumors and its product may be processed into different isoforms, some of which have been demonstrated to possess transforming activity. In a panel of liposarcomas characterized by displaying 4 different combinations of mdm2/p53 immunoreactivity, molecular analysis of amplified MDM2 gene revealed a coexistence of mutated full-length MDM2 messenger RNAs, an out-of-frame splicing mRNA and finally aberrant spliced forms. Two of the latter are reported here for the first time. The molecular differences in this heterogeneous mRNA population seem to mirror distinct functional aspects of the altered encoded mdm2 proteins. In fact, besides the deleted transcripts defective in their ability to bind p53 and known to possess a transforming activity, here we describe both mutated full-length forms and deleted transcripts that still maintain the ability to bind p53 but, based on their mdm2+/p53+ immunophenotype, probably fail to signal its degradation. These aberrant forms, which are responsible for the accumulation and inactivation of p53, can contribute, together with the p53 independent transforming forms, to liposarcoma transforming pathway.
Tamborini
E
E
Laboratory of Molecular Diagnosis, Department of Pathology and Cytopathology, Istituto Nazionale per lo Studio e la Cura dei Tumori, Via G. Venezian, Milano, Italy. tamborini@istitutotumori.mi.it
Della Torre
G
G
Lavarino
C
C
Azzarelli
A
A
Carpinelli
P
P
Pierotti
M A
MA
Pilotti
S
S
D000008:Abdominal Neoplasms / Q000235:genetics / Q000378:metabolism; D000273:Adipose Tissue / Q000378:metabolism; D017398:Alternative Splicing; D015139:Blotting, Southern; D003001:Cloning, Molecular; D003106:Colon / Q000378:metabolism; D017353:Gene Deletion; D016158:Genes, p53 / Q000235:genetics*; D006801:Humans; D016130:Immunophenotyping; D008080:Liposarcoma / Q000378:metabolism*; D008957:Models, Genetic; D009154:Mutation; D009687:Nuclear Proteins; D010534:Peritoneal Neoplasms / Q000235:genetics / Q000378:metabolism; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D011233:Precipitin Tests; D014176:Protein Biosynthesis; D020033:Protein Isoforms; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism*; D051736:Proto-Oncogene Proteins c-mdm2; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017422:Sequence Analysis, DNA; D012878:Skin Neoplasms / Q000235:genetics / Q000378:metabolism; D013899:Thoracic Neoplasms / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D009687:Nuclear Proteins; D020033:Protein Isoforms; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2