title: In vivo functional studies of tumor-specific retrogene NanogP8 in transgenic animals.
abstract: The current study was undertaken to investigate potential oncogenic functions of NanogP8, a tumor-specific retrogene homolog of Nanog (expressed in pluripotent cells), in transgenic animal models. To this end, human primary prostate tumor-derived NanogP8 was targeted to the cytokeratin 14 (K14) cellular compartment, and two lines of K14-NanogP8 mice were derived. The line 1 animals, expressing high levels of NanogP8, experienced perinatal lethality and developmental abnormalities in multiple organs, including the skin, tongue, eye, and thymus in surviving animals. On postnatal day 5 transgenic skin, for example, there was increased c-Myc expression and Ki-67(+) cells accompanied by profound abnormalities in skin development such as thickened interfollicular epidermis and dermis and lack of hypodermis and sebaceous glands. The line 3 mice, expressing low levels of NanogP8, were grossly normal except cataract development by 4-6 mo of age. Surprisingly, both lines of mice do not develop spontaneous tumors related to transgene expression. Even more unexpectedly, high levels of NanogP8 expression in L1 mice actually inhibited tumor development in a two-stage chemical carcinogenesis model. Mechanistic studies revealed that constitutive NanogP8 overexpression in adult L1 mice reduced CD34(+)α6(+) and Lrig-1(+) bulge stem cells, impaired keratinocyte migration, and repressed the expression of many stem cell-associated genes, including Bmp5, Fgfr2, Jmjd1a, and Jun. Our study, for the first time, indicates that transgenically expressed human NanogP8 is biologically functional, but suggests that high levels of NanogP8 may disrupt normal developmental programs and inhibit tumor development by depleting stem cells.
authors.affiliation: Department of Molecular Carcinogenesis; University of Texas MD Anderson Cancer Center; Smithville, TX USA; Program in Molecular Carcinogenesis; University of Texas Graduate School of Biomedical Sciences (GSBS); Houston, TX USA.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Badeaux
authors.forename: Collene R
authors.initials: CR
authors.lastname: Jeter
authors.forename: Shuai
authors.initials: S
authors.lastname: Gong
authors.forename: Bigang
authors.initials: B
authors.lastname: Liu
authors.forename: Mahipal V
authors.initials: MV
authors.lastname: Suraneni
authors.forename: Joyce
authors.initials: J
authors.lastname: Rundhaug
authors.forename: Susan M
authors.initials: SM
authors.lastname: Fischer
authors.forename: Tao
authors.initials: T
authors.lastname: Yang
authors.forename: Donna
authors.initials: D
authors.lastname: Kusewitt
authors.forename: Dean G
authors.initials: DG
authors.lastname: Tang
mesh_terms: D015127:9,10-Dimethyl-1,2-benzanthracene; D000818:Animals; D002465:Cell Movement; D004848:Epithelium / Q000378:metabolism / Q000473:pathology; D005260:Female; D018398:Homeodomain Proteins / Q000096:biosynthesis / Q000235:genetics*; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D000071317:Nanog Homeobox Protein; D010212:Papilloma / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D010641:Phenotype; D012867:Skin / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D012878:Skin Neoplasms / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D014059:Tongue / Q000378:metabolism / Q000473:pathology; D014945:Wound Healing
chemical_list: D018398:Homeodomain Proteins; C486780:NANOG protein, human; D000071317:Nanog Homeobox Protein; D015127:9,10-Dimethyl-1,2-benzanthracene
keywords: K14; NanogP8; epidermis; stem cells; tumor development