Alternatively spliced mdm2 transcripts with loss of p53 binding domain sequences: transforming ability and frequent detection in human cancer.
The mdm2 oncogene encodes a 90-kilodalton nuclear phosphoprotein that binds and inactivates the p53 tumor suppressor protein. Here we report the observation of five alternatively spliced mdm2 gene transcripts in a range of human cancers and their absence in normal tissues. Transfection of NIH 3T3 cells with each of these forms gave foci of morphologically transformed cells. A higher frequency of splice variants lacking p53 binding domain sequences was found in late-stage and high-grade ovarian and bladder carcinomas. Four of the splice variants show loss of p53 binding, consistent with partial deletion of sequences encoding the p53 binding domain, but retain carboxyterminal zinc-finger domains. These observations suggest a reassessment of the transforming mechanisms of mdm2 and its relation to p53.
Sigalas
I
I
Cancer Research Unit, The Medical School, University of Newcastle upon Tyne, Framlington Place, UK.
Calvert
A H
AH
Anderson
J J
JJ
Neal
D E
DE
Lunec
J
J
D016475:3T3 Cells; D017398:Alternative Splicing; D000818:Animals; D001483:Base Sequence; D002471:Cell Transformation, Neoplastic; D017931:DNA Primers; D018450:Disease Progression; D005260:Female; D006801:Humans; D007938:Leukemia / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D009687:Nuclear Proteins; D010051:Ovarian Neoplasms / Q000378:metabolism / Q000473:pathology; D011485:Protein Binding; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2; D012313:RNA / Q000378:metabolism; D014170:Transformation, Genetic; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D001749:Urinary Bladder Neoplasms / Q000378:metabolism / Q000473:pathology
D017931:DNA Primers; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; D012313:RNA; C497206:MDM2 protein, human; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2