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PMID: 19272531 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S.

Abnormal differentiation, hyperplasia and embryonic/perinatal lethality in BK5-T/t transgenic mice.

Differentiation; research in biological diversity ·Vol. 77 ·No. 3 ·2009-03-00 ·Pages 324-34

Chen X, Schneider-Broussard R, Hollowell D, McArthur M, Jeter CR, Benavides F, DiGiovanni J, Tang DG

Abstract

The cell-of-origin has a great impact on the types of tumors that develop and the stem/progenitor cells have long been considered main targets of malignant transformation. The SV40 (SV40-Simian Virus 40) large T and small t antigens (T/t), have been targeted to multiple-differentiated cellular compartments in transgenic mice. In most of these studies, transgenic animals develop tumors without apparent defects in animal development. In this study, we used the bovine keratin 5 (BK5) promoter to target the T/t antigens to stem/progenitor cell-containing cytokeratin 5 (CK5) cellular compartment. A transgene construct, BK5-T/t, was made and microinjected into the male pronucleus of FVB/N mouse oocytes. After implanting approximately 1700 embryos, only 7 transgenics were obtained, including 4 embryos (E9.5, E13, E15, and E20) and 3 postnatal animals, which died at P1, P2, and P18, respectively. Immunohistological analysis revealed aberrant differentiation and prominent hyperplasia in several transgenic CK5 tissues, especially the upper digestive organs (tongue, oral mucosa, esophagus, and forestomach) and epidermis, the latter of which also showed focal dysplasia. Altogether, these results indicate that constitutive expression of the T/t antigens in CK5 cellular compartment results in abnormal epithelial differentiation and leads to embryonic/perinatal animal lethality.

MeSH Terms
Animals Antigens, Polyomavirus Transforming/metabolism Apoptosis Cell Differentiation Epidermis/metabolism,pathology Epithelial Cells/cytology,metabolism Gastrointestinal Tract/pathology Gene Expression Regulation Hyperplasia/metabolism Keratin-5/genetics,metabolism Male Mice Mice, Transgenic Promoter Regions, Genetic Simian virus 40/genetics,metabolism Tongue/metabolism,pathology
Chemicals
Antigens, Polyomavirus Transforming Keratin-5
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Chen Xin
Department of Carcinogenesis, The University of Texas M.D. Anderson Cancer Center, Science Park-Research Division, 1808 Park Road 1-C, P.O. Box 389, Smithville, TX 78957, USA.
Schneider-Broussard Robin
Hollowell Debra
McArthur Mark
Jeter Collene R
Benavides Fernando
DiGiovanni John
Tang Dean G
References (41)
41 references, click to expand
  1. Evaluation of the oral toxicity of acetaldehyde and formaldehyde in a 4-week drinking-water study in rats.
    Food Chem Toxicol. 1988 May;26(5):447-52 PMID: 3391468
  2. Probing keratinocyte and differentiation specificity of the human K5 promoter in vitro and in transgenic mice.
    Mol Cell Biol. 1993 Jun;13(6):3176-90 PMID: 7684490
  3. Evidence that senescent human prostate epithelial cells enhance tumorigenicity: cell fusion as a potential mechanism and inhibition by p16INK4a and hTERT.
    Int J Cancer. 2008 Apr 1;122(7):1483-95 PMID: 18059027
  4. Abnormal differentiation of epidermis in transgenic mice constitutively expressing cyclooxygenase-2 in skin.
    Proc Natl Acad Sci U S A. 2001 Jun 19;98(13):7629-34 PMID: 11381142
  5. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell.
    Nat Med. 1997 Jul;3(7):730-7 PMID: 9212098
  6. Mutation analysis of the entire keratin 5 and 14 genes in patients with epidermolysis bullosa simplex and identification of novel mutations.
    Hum Mutat. 2003 Apr;21(4):447 PMID: 12655565
  7. Prostate cancer in a transgenic mouse.
    Proc Natl Acad Sci U S A. 1995 Apr 11;92(8):3439-43 PMID: 7724580
  8. The malignant capacity of skin tumours induced by expression of a mutant H-ras transgene depends on the cell type targeted.
    Curr Biol. 1998 Apr 23;8(9):516-24 PMID: 9560338
  9. E2F1 has both oncogenic and tumor-suppressive properties in a transgenic model.
    Mol Cell Biol. 1999 Sep;19(9):6408-14 PMID: 10454586
  10. Stem cells, cancer, and cancer stem cells.
    Nature. 2001 Nov 1;414(6859):105-11 PMID: 11689955
  11. Epithelial-mesenchymal transformation during craniofacial development.
    J Dent Res. 2005 Aug;84(8):678-90 PMID: 16040723
  12. Female mice chimeric for expression of the simian virus 40 TAg under control of the MISIIR promoter develop epithelial ovarian cancer.
    Cancer Res. 2003 Mar 15;63(6):1389-97 PMID: 12649204
  13. Complete cytolysis and neonatal lethality in keratin 5 knockout mice reveal its fundamental role in skin integrity and in epidermolysis bullosa simplex.
    Mol Biol Cell. 2001 Jun;12(6):1775-89 PMID: 11408584
  14. Targeted expression of c-Src in epidermal basal cells leads to enhanced skin tumor promotion, malignant progression, and metastasis.
    Cancer Res. 2003 Aug 15;63(16):4819-28 PMID: 12941801
  15. Immunohistochemical expression of keratins 13 and 14 in the lingual epithelium of rats during the morphogenesis of filiform papillae.
    Arch Oral Biol. 2006 May;51(5):416-26 PMID: 16271699
  16. Induction of epidermal hyperplasia, hyperkeratosis, and papillomas in transgenic mice by a targeted v-Ha-ras oncogene.
    Mol Carcinog. 1993;7(2):99-110 PMID: 7681293
  17. Skin hyperkeratosis and papilloma formation in transgenic mice expressing a ras oncogene from a suprabasal keratin promoter.
    Cell. 1990 Aug 24;62(4):697-708 PMID: 1696852
  18. Prospective identification of tumorigenic breast cancer cells.
    Proc Natl Acad Sci U S A. 2003 Apr 1;100(7):3983-8 PMID: 12629218
  19. Transgenic expression of cyclin D1 in thymic epithelial precursors promotes epithelial and T cell development.
    J Immunol. 2000 Feb 15;164(4):1881-8 PMID: 10657637
  20. Evidence for stem cells in cultures of mouse prostate epithelial cells.
    Prostate. 2002 Jan 1;50(1):46-53 PMID: 11757035
  21. Sequences 5' of the bovine keratin 5 gene direct tissue- and cell-type-specific expression of a lacZ gene in the adult and during development.
    Differentiation. 1994 Nov;58(1):53-64 PMID: 7532601
  22. The basal keratin network of stratified squamous epithelia: defining K15 function in the absence of K14.
    J Cell Biol. 1995 Jun;129(5):1329-44 PMID: 7539810
  23. Defining the epithelial stem cell niche in skin.
    Science. 2004 Jan 16;303(5656):359-63 PMID: 14671312
  24. Identification of a subpopulation of cells with cancer stem cell properties in head and neck squamous cell carcinoma.
    Proc Natl Acad Sci U S A. 2007 Jan 16;104(3):973-8 PMID: 17210912
  25. Programming gene expression in developing epidermis.
    Development. 1994 Sep;120(9):2369-83 PMID: 7525178
  26. Unique and overlapping functions of pRb and p107 in the control of proliferation and differentiation in epidermis.
    Development. 2004 Jun;131(11):2737-48 PMID: 15148303
  27. Prostate and mammary adenocarcinoma in transgenic mice carrying a rat C3(1) simian virus 40 large tumor antigen fusion gene.
    Proc Natl Acad Sci U S A. 1994 Nov 8;91(23):11236-40 PMID: 7972041
  28. Transgenic mouse model for neurocristopathy: Schwannomas and facial bone tumors.
    Proc Natl Acad Sci U S A. 1993 Apr 15;90(8):3192-6 PMID: 8386366
  29. Requirement for a functional Rb-1 gene in murine development.
    Nature. 1992 Sep 24;359(6393):328-30 PMID: 1406937
  30. Stem-cell hierarchy in skin cancer.
    Nat Rev Cancer. 2003 Jun;3(6):434-43 PMID: 12778133
  31. Involvement of PP2A in viral and cellular transformation.
    Oncogene. 2005 Nov 21;24(52):7746-55 PMID: 16299534
  32. Cell-autonomous induction of functional tumor suppressor 15-lipoxygenase 2 (15-LOX2) contributes to replicative senescence of human prostate progenitor cells.
    Oncogene. 2005 May 19;24(22):3583-95 PMID: 15750631
  33. Cyclin-dependent kinase inhibitor expression in pulmonary Clara cells transformed with SV40 large T antigen in transgenic mice.
    Cell Growth Differ. 1997 Feb;8(2):145-55 PMID: 9040936
  34. Highly purified CD44+ prostate cancer cells from xenograft human tumors are enriched in tumorigenic and metastatic progenitor cells.
    Oncogene. 2006 Mar 16;25(12):1696-708 PMID: 16449977
  35. SV40 large T antigen targets multiple cellular pathways to elicit cellular transformation.
    Oncogene. 2005 Nov 21;24(52):7729-45 PMID: 16299533
  36. Transitional cell hyperplasia and carcinomas in urinary bladders of transgenic mice with keratin 5 promoter-driven cyclooxygenase-2 overexpression.
    Cancer Res. 2005 Mar 1;65(5):1808-13 PMID: 15753378
  37. Keratin function in skin epithelia: a broadening palette with surprising shades.
    Curr Opin Cell Biol. 2007 Feb;19(1):13-23 PMID: 17178453
  38. Transformation of different human breast epithelial cell types leads to distinct tumor phenotypes.
    Cancer Cell. 2007 Aug;12(2):160-70 PMID: 17692807
  39. Identification of an integrated SV40 T/t-antigen cancer signature in aggressive human breast, prostate, and lung carcinomas with poor prognosis.
    Cancer Res. 2007 Sep 1;67(17):8065-80 PMID: 17804718
  40. The mitogen-activated protein kinase kinase kinase dual leucine zipper-bearing kinase (DLK) acts as a key regulator of keratinocyte terminal differentiation.
    J Biol Chem. 2005 Apr 1;280(13):12732-41 PMID: 15695824
  41. Common adult stem cells in the human breast give rise to glandular and myoepithelial cell lineages: a new cell biological concept.
    Lab Invest. 2002 Jun;82(6):737-46 PMID: 12065684
Article Info
Journal
Differentiation; research in biological diversity
Abbr.
Differentiation
ISSN
1432-0436
DOI
10.1016/j.diff.2008.10.011
Published
2009-03-00
Epub
2008-00-21
Pages
324-34
Language
English
Region
England
NLM ID
0401650
PMCID
PMC2680132
Subset
IM
Grants
NIA NIH HHS · R01 AG023374-03 · United States
NIA NIH HHS · R01-AG023374 · United States
NCI NIH HHS · P30 CA016672 · United States
NIA NIH HHS · R01 AG023374-01A1 · United States
NIA NIH HHS · R01 AG023374-02 · United States
NIA NIH HHS · R01 AG023374 · United States
NIEHS NIH HHS · R21 ES015893-02 · United States
NCI NIH HHS · R01 CA166672 · United States
NIEHS NIH HHS · R21 ES015893 · United States
NCI NIH HHS · P30 CA016672-33 · United States
NIEHS NIH HHS · R01 ES015888-02 · United States
NCI NIH HHS · P30 CA016672-24 · United States
NIEHS NIH HHS · P30 ES007784 · United States
NCI NIH HHS · P30 CA016672-33S1 · United States
NIEHS NIH HHS · P30 ES007784-12 · United States
NIEHS NIH HHS · R01 ES015888-01 · United States
NIEHS NIH HHS · ES07784 · United States
NIEHS NIH HHS · R01-ES015888 · United States
NIA NIH HHS · R01 AG023374-05 · United States
NIEHS NIH HHS · R01 ES015888 · United States
NIA NIH HHS · R01 AG023374-04 · United States
NCI NIH HHS · P30 CA166672 · United States
NIEHS NIH HHS · R21 ES015893-01A1 · United States
External Links
PubMed source DOI: 10.1016/j.diff.2008.10.011 PMC Full Text View journal details
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