Allen Carl E, Muthusamy Natarajan, Weisbrode Steven E, Hong Joung Woo, Wu Lai-Chu
Program of Molecular, Cellular, and Developmental Biology, College of Medicine and Public Health, The Ohio State University, Columbus, Ohio, USA.
Genes Chromosomes Cancer. 2002 Dec;35(4):287-98. doi: 10.1002/gcc.10128.
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.
大型锌指蛋白KRC与V(D)J重组的信号序列及κB基序结合。细胞系中KRC表达的破坏导致细胞增殖增加、生长的锚定非依赖性以及核分裂与细胞分裂的解偶联。在本报告中，在RAG2缺陷的囊胚互补动物模型中研究了KRC的功能。通过同源重组产生了KRC缺陷的胚胎干细胞，并将其导入RAG2(-/-)囊胚中以产生KRC(-/-);RAG2(-/-)嵌合小鼠。对5周龄嵌合体的淋巴区室进行检查，发现其已发育，这表明KRC对于V(D)J重组的发育并非必不可少。然而，到6个月龄时，嵌合体中的CD4(+)CD8(+)胸腺细胞出现明显缺陷，这表明KRC可能参与T淋巴细胞的存活。此外，一只嵌合体出现了异常，包括轴后多指畸形、肾积水和性腺外恶性畸胎瘤。DNA分析表明，畸胎瘤源自KRC(-/-)胚胎干细胞。畸胎瘤具有复合组织结构，并被B淋巴细胞浸润。随后，从畸胎瘤中建立了几种永生化的KRC缺陷细胞系。在本研究中，在KRC缺陷的动物和细胞中观察到生长异常和肿瘤形成，并且其他研究表明在各种肿瘤中人类KRC对应物的染色体区域发生了等位基因缺失。我们提出KRC可能是一个先前未被鉴定的肿瘤抑制基因。
