title: Generation of a mouse model for studying the role of upregulated RTEL1 activity in tumorigenesis.
abstract: Regulator of telomere length 1 (RTEL1) is a DNA helicase protein that has been demonstrated to be required for the maintenance of telomere length and genomic stability. It has also been found to be essential for DNA homologous recombination during DNA repairing. Human RTEL1 genomic locus (20q13.3) is frequently amplified in multiple types of human cancers, including hepatocellular carcinoma and gastrointestinal tract tumors, indicating that upregulated RTEL1 activity could be important for tumorigenesis. In this study, we have developed a conditional transgenic mouse model that overexpress mouse Rtel1 in a Cre-excision manner. By crossing with a ubiquitous Cre mouse line, we further demonstrated that these established Rtel1 conditional transgenic mice allow to efficiently and highly express a functional Rtel1 that is able to rescue the embryonic defects of Rtel1 null mouse allele. Furthermore, we demonstrated that more than 70% transgenic mice that widely overexpress Rtel1 developed liver tumors that recapitulate many malignant features of human hepatocellular carcinoma (HCC). Our work not only generated a valuable mouse model for determining the role of RTEL1 in the development of cancers, but also provided the first genetic evidence to support that amplification of RTEL1, as observed in several types of human cancers, is tumorigenic.
authors.affiliation: Department of Biochemistry and Medical Genetics, University of Manitoba, 745 Bannatyne Avenue, R3E 0J9, Winnipeg, MB, Canada.
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Wu
authors.forename: Sumit
authors.initials: S
authors.lastname: Sandhu
authors.forename: Zinnatun
authors.initials: Z
authors.lastname: Nabi
authors.forename: Hao
authors.initials: H
authors.lastname: Ding
mesh_terms: D000483:Alleles; D000818:Animals; D002471:Cell Transformation, Neoplastic; D002678:Chimera / Q000378:metabolism; D003433:Crosses, Genetic; D004265:DNA Helicases / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D018274:Electroporation; D053595:Embryonic Stem Cells / Q000378:metabolism / Q000473:pathology; D004789:Enzyme Activation; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D005822:Genetic Vectors / Q000235:genetics / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology; D007150:Immunohistochemistry; D008113:Liver Neoplasms / Q000235:genetics / Q000473:pathology*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008822:Mice, Transgenic
chemical_list: C527736:regulator of telomere length protein, mouse; D004265:DNA Helicases