Reduced expression of the cyclin-dependent kinase inhibitor gene p57KIP2 in Wilms' tumor.
We have previously shown that the p57KIP2 gene, which encodes a cyclin-dependent kinase inhibitor, undergoes genomic imprinting and lies within a 700-kb domain of imprinted genes on 11p15, including IGF2 and H19. Loss of heterozygosity and loss of imprinting (LOI) of this region are frequently observed in Wilms' tumor (WT) and other embryonal malignancies. Although LOI of p57KIP2 was observed in some WTs (approximately 10%), allele-specific expression was preserved in most tumors examined. Because our initial studies were inconclusive concerning the absolute expression level of p57KIP2 in WT, we developed a sensitive and quantitative RNase protection assay to determine if changes in p57KIP2 expression play a role in WT. Expression of p57KIP2 was found to be virtually absent in 21 of 21 WTs compared to matched normal kidney from the same patients, as well as compared to fetal kidney. We also examined p57KIP2 expression in the normal kidney and tongue of patients with Beckwith-Wiedemann syndrome (BWS), which predisposes to WT and also involves LOI of IGF2 and H19. Although p57KIP2 was undetectable in BWS tongue, similar results were also observed in postnatal non-BWS tongue samples. Most primary skin fibroblast cultures of BWS cell lines exhibited normal imprinting of p57KIP2. However, one BWS patient did show LOI of p57KIP2 in skin fibroblasts. Thus, p57KIP2 is part of a domain of genes on 11p15 that show altered expression and, in some cases, altered imprinting in WT and BWS.
Thompson
J S
JS
Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
Reese
K J
KJ
DeBaun
M R
MR
Perlman
E J
EJ
Feinberg
A P
AP
D001506:Beckwith-Wiedemann Syndrome / Q000201:enzymology / Q000235:genetics*; D050761:Cyclin-Dependent Kinase Inhibitor p57; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D017353:Gene Deletion; D006801:Humans; D007680:Kidney Neoplasms / Q000201:enzymology / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D009396:Wilms Tumor / Q000201:enzymology / Q000235:genetics*
C493964:CDKN1C protein, human; D050761:Cyclin-Dependent Kinase Inhibitor p57; D009687:Nuclear Proteins; D018844:Cyclin-Dependent Kinases