正常絨毛における増殖・分化調節の分子機構(2 ヒト絨毛細胞の機能とその異常)

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The aim of this study was to analyze molecular mechanisms involved in the proliferation and differentiation of normal villous trophoblast. We studied the genetic features of hydatidiform moles(HM)and choriocarcinomas(CC), which are examples of deviation from normal control of proliferation and differentiation. Both HM and CC that originate from normal trophoblast are characterized by monoallelic contribution from the paternal genome. We investigated molecular mechanisms of proliferation and differentiation in HM and CC, as they relate to genome imprinting, proliferative control of trophoblast and tumor suppressor mechanisms. Genome imprinting is one of the most improtant mechanisms in the development of the placenta in mammals. Both the maternal and paternal genomes are necessary for normal embryonic and extraembryonic development. Analysis of imprinted gene expression in mouse placenta using in situ hybridization revealed that 8 of the 10 imprinted genes examined in the present study were expressed in the placental tissues of 7.5 dpc mouse embryos. Maternal-origin-specific expression was observed in the ectoplacental cone, and was diminished in the spongiotrophoblast layer at 13.5 dpc. These findings indicate that originspecific functional differences between alleles are due to a regulatory epigenetic mechanism crucial for the proper development of extraembryonic tissues. Previous genetic analysis has indicated that HM is caused by overexpression of proliferation genes in trophoblastic cells. In the present study, we adopted a new strategy in searching for genes associated with HM, which served as a model of overproliferation in trophoblasts. We isolated and identified the genes that are expressed in HM but not in normal villi, using a DAN microarray and subtraction methods. The genes thus isolated suggest that signal transduction-associated genes are important for normal villous proliferation. We focused on the genes of signal transduction, especially those associated with the JAK(Janus kinase)-STAT(signal transducers and activators of transcription)signal transduction system. Microarray analysis revealed that expression of STAT5b, one on the STAT genes, was increased in HM, and that expression on the SOCS(suppressor of cytokine signal)-1 gene, the inhibitor on the SATA signal, was decreased in HM. The expression patterns of these 2 genes indicate that JAK-STAT system plays a crucial role in normal trophoblastic proliferation, and that HM may be caused by overstimulation of this system. We also examined mechanisms of choriocarcinoma, which is an example of deviation from normal trophoblastic differentiation. Using subtraction and positional cloning, we isolated 2 putative choriocarcinoma suppressor genes. The gene SMAP-S31 exhibits in vivo tumor suppressor activity. It has a region homologous to the homeodomain of homeobox genes, and is located at chromosomal position 4q11-12(as revealed by FISH). Positional cloning also revealed a homozygous deletion at human chromosome 7 in choriocarcinoma tissue. From this deleted region, we isolated bacterial artificial chromosome(BAC)clones and cDNA clones to identify the critical site of tumor suppressor activity. Some clones from this deleted region suppressed tumorigenicity of choriocarcinoma. This suppression was demonstrated by transfecting clones into a choriocarcinoma cell line via an expression vector. SMAP-C6-8, cloned from a human cDNA library, is a putative choriocarcinoma suppressor gene that contains a leucine zipper(a structure found in transcription factors). Based on these results, we propose a new genetic model of normal proliferation and differentiation in human trophoblast.
社団法人日本産科婦人科学会の論文
2001-09-01

正常絨毛における増殖・分化調節の分子機構(2 ヒト絨毛細胞の機能とその異常)

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