Developmental anomalies and neoplasia in animals and cells deficient in the large zinc finger protein KRC.
The large zinc finger protein KRC binds to the signal sequences of V(D)J recombination and the kappaB motif. Disruption of KRC expression in cell lines resulted in increased cell proliferation, anchorage independence of growth, and uncoupling of nuclear division and cell division. In this report, the function of KRC was studied in a RAG2-deficient blastocyst complementation animal model. KRC-deficient embryonic stem cells were generated by homologous recombination and were introduced into RAG2(-/-) blastocysts to generate KRC(-/-);RAG2(-/-) chimeric mice. The lymphoid compartments of chimeras examined at 5 weeks of age were developed, suggesting that KRC is not essential for V(D)J recombination development. However, by 6 months of age, there was a marked deficit in CD4(+)CD8(+) thymocytes in the chimeras, suggesting that KRC may be involved in T-lymphocyte survival. Additionally, one chimera developed anomalies, including postaxial polydactyly, hydronephrosis, and an extragonadal malignant teratoma. DNA analysis showed that the teratoma was derived from KRC(-/-) embryonic stem cells. The teratoma had compound tissue organization and was infiltrated with B lymphocytes. Subsequently, several immortalized KRC-deficient cell lines were established from the teratoma. In this study, growth anomalies and neoplasia were observed in animals and cells deficient in KRC, and other studies have shown allelic loss occurring at the chromosomal region of the human KRC counterpart in various tumors. We propose that KRC may be a previously unidentified tumor-suppresser gene.
Allen
Carl E
CE
Program of Molecular, Cellular, and Developmental Biology, College of Medicine and Public Health, The Ohio State University, Columbus, Ohio, USA.
Muthusamy
Natarajan
N
Weisbrode
Steven E
SE
Hong
Joung Woo
JW
Wu
Lai-Chu
LC
D000015:Abnormalities, Multiple / Q000235:genetics*; D000818:Animals; D002678:Chimera / Q000235:genetics; D004268:DNA-Binding Proteins / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D005260:Female; D016147:Genes, Tumor Suppressor; D005822:Genetic Vectors / Q000235:genetics; D006130:Growth Disorders / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D013234:Stem Cells / Q000737:chemistry / Q000378:metabolism; D013724:Teratoma / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D013899:Thoracic Neoplasms / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D014407:Tumor Cells, Cultured; D016335:Zinc Fingers / Q000235:genetics*
D004268:DNA-Binding Proteins; C084779:Hivep3 protein, mouse; C499308:Rag2 protein, mouse; C064655:V(D)J recombination activating protein 2