Home LiteratureArticle Details
PMID: 18986660 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Human papillomavirus 16 E6 variants differ in their dysregulation of human keratinocyte differentiation and apoptosis.

Virology ·Vol. 383 ·No. 1 ·2009-01-05 ·Pages 69-77

Zehbe I, Richard C, DeCarlo CA, Shai A, Lambert PF, Lichtig H, Tommasino M, Sherman L

Abstract

L83V-related variants of human papillomavirus (HPV) 16 E6, exemplified by the Asian-American variant Q14H/H78Y/L83V, were shown to be more prevalent than E6 prototype in progressing lesions and cervical cancer. We evaluated functions relevant to carcinogenesis for the E6 variants L83V, R10/L83V and Q14H/H78Y/L83V as well as the prototype in a model of human normal immortalized keratinocytes (NIKS). All E6 expressing NIKS equally abrogated growth arrest and DNA damage responses. Organotypic cultures derived from these keratinocytes demonstrated hyperplasia and aberrantly expressed keratin 5 in the suprabasal compartment. In contrast, differentiation and induction of apoptosis varied. The E6 variant rafts expressed keratin 10 in nearly all suprabasal cells while the prototype raft showed keratin 10 staining in a subset of suprabasal cells only. In addition, E6 variant NIKS expressing R10G/L83V and Q14H/H78Y/L83V were more prone to undergo cell-detachment-induced apoptosis (anoikis) than NIKS expressing E6 prototype. The combined differentiation and apoptosis pattern of high-risk E6 variants, especially of Q14H/H78Y/L83V, may reflect a phenotype beneficial to carcinogenesis and viral life cycle.

MeSH Terms
Apoptosis Cell Differentiation Cell Transformation, Viral Cells, Cultured Female Genetic Variation Human papillomavirus 16/genetics,physiology Humans Keratinocytes/virology Oncogene Proteins, Viral/genetics,metabolism Repressor Proteins/genetics,metabolism
Chemicals
E6 protein, Human papillomavirus type 16 Oncogene Proteins, Viral Repressor Proteins
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Zehbe Ingeborg
Thunder Bay Regional Health Sciences Centre, Regional Cancer Care, Thunder Bay, Ontario, Canada P7B 6V4. zehbei@tbh.net
Richard Christina
DeCarlo Correne A
Shai Anny
Lambert Paul F
Lichtig Hava
Tommasino Massimo
Sherman Levana
References (70)
70 references, click to expand
  1. Human papillomavirus genotype as a predictor of persistence and development of high-grade lesions in women with minor cervical abnormalities.
    Int J Cancer. 1996 Oct 21;69(5):364-8 PMID: 8900368
  2. 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
  3. Role of the PDZ domain-binding motif of the oncoprotein E6 in the pathogenesis of human papillomavirus type 31.
    J Virol. 2004 Nov;78(22):12366-77 PMID: 15507623
  4. Human papillomavirus type 16 DNA sequence.
    Virology. 1985 Aug;145(1):181-5 PMID: 2990099
  5. Improved program for the analysis of DNA histograms.
    Cytometry. 1987 Nov;8(6):637-41 PMID: 3428045
  6. Stabilization of type I topoisomerase-DNA covalent complexes by actinomycin D.
    Proc Natl Acad Sci U S A. 1988 Mar;85(5):1417-21 PMID: 2830618
  7. Papillomaviruses and cancer: from basic studies to clinical application.
    Nat Rev Cancer. 2002 May;2(5):342-50 PMID: 12044010
  8. The human papillomavirus 16 E6 protein binds to tumor necrosis factor (TNF) R1 and protects cells from TNF-induced apoptosis.
    J Biol Chem. 2002 Jun 14;277(24):21730-9 PMID: 11934887
  9. Down regulation of the interleukin-8 promoter by human papillomavirus type 16 E6 and E7 through effects on CREB binding protein/p300 and P/CAF.
    J Virol. 2002 Sep;76(17):8710-21 PMID: 12163591
  10. Human papillomavirus type-16 variants in Quechua aboriginals from Argentina.
    J Med Virol. 2003 Apr;69(4):546-52 PMID: 12601763
  11. Human papillomavirus E6 and Myc proteins associate in vivo and bind to and cooperatively activate the telomerase reverse transcriptase promoter.
    Proc Natl Acad Sci U S A. 2003 Jul 8;100(14):8211-6 PMID: 12821782
  12. Molecular variants of HPV type 16 E6 among Mexican women with LSIL and invasive cancer.
    J Clin Virol. 2004 Feb;29(2):95-8 PMID: 14747027
  13. Human papillomavirus type 16 sequence variation in cervical cancers: a worldwide perspective.
    J Virol. 1997 Mar;71(3):2463-72 PMID: 9032384
  14. Genomic variation of human papillomavirus type 16 and risk for high grade cervical intraepithelial neoplasia.
    J Natl Cancer Inst. 1997 Jun 4;89(11):796-802 PMID: 9182978
  15. Human papillomavirus 16 E6 variants are more prevalent in invasive cervical carcinoma than the prototype.
    Cancer Res. 1998 Feb 15;58(4):829-33 PMID: 9485042
  16. Risk of cervical cancer and geographical variations of human papillomavirus 16 E6 polymorphisms.
    Lancet. 1998 Oct 31;352(9138):1441-2 PMID: 9807995
  17. HPV16 E6 oncoprotein inhibits apoptosis induced during serum-calcium differentiation of foreskin human keratinocytes.
    Virology. 1999 May 10;257(2):383-96 PMID: 10329549
  18. The human papillomavirus type 16 E6 gene alone is sufficient to induce carcinomas in transgenic animals.
    J Virol. 1999 Jul;73(7):5887-93 PMID: 10364340
  19. The E6 protein of human papillomavirus type 16 binds to and inhibits co-activation by CBP and p300.
    EMBO J. 1999 Sep 15;18(18):5061-72 PMID: 10487758
  20. Establishment of the human papillomavirus type 16 (HPV-16) life cycle in an immortalized human foreskin keratinocyte cell line.
    Virology. 1999 Sep 30;262(2):344-54 PMID: 10502513
  21. The E6 oncoprotein encoded by human papillomavirus types 16 and 18 promotes the degradation of p53.
    Cell. 1990 Dec 21;63(6):1129-36 PMID: 2175676
  22. Altered regulation of growth and expression of differentiation-associated keratins in benign mouse skin tumors.
    Carcinogenesis. 1991 Nov;12(11):2063-7 PMID: 1718620
  23. The E6 and E7 genes of human papillomavirus type 6 have weak immortalizing activity in human epithelial cells.
    J Virol. 1992 Apr;66(4):2125-34 PMID: 1312623
  24. Recombinant retroviruses encoding human papillomavirus type 18 E6 and E7 genes stimulate proliferation and delay differentiation of human keratinocytes early after infection.
    Oncogene. 1992 Apr;7(4):619-26 PMID: 1314365
  25. Human papillomavirus 16 E6 expression disrupts the p53-mediated cellular response to DNA damage.
    Proc Natl Acad Sci U S A. 1993 May 1;90(9):3988-92 PMID: 8387205
  26. Commitment to differentiation and expression of early differentiation markers in murine keratinocytes in vitro are regulated independently of extracellular calcium concentrations.
    J Cell Biol. 1993 Nov;123(4):909-19 PMID: 7693721
  27. The ability of human papillomavirus E6 proteins to target p53 for degradation in vivo correlates with their ability to abrogate actinomycin D-induced growth arrest.
    J Virol. 1994 Sep;68(9):5698-705 PMID: 8057451
  28. Analysis of human papillomavirus type 16 variants indicates establishment of persistent infection.
    J Infect Dis. 1995 Sep;172(3):747-55 PMID: 7658068
  29. Human papillomavirus type 16 alters human epithelial cell differentiation in vitro.
    Proc Natl Acad Sci U S A. 1988 Oct;85(19):7169-73 PMID: 2459699
  30. Immortalization and altered differentiation of human keratinocytes in vitro by the E6 and E7 open reading frames of human papillomavirus type 18.
    J Virol. 1990 Feb;64(2):519-26 PMID: 2153221
  31. Advanced mammalian gene transfer: high titre retroviral vectors with multiple drug selection markers and a complementary helper-free packaging cell line.
    Nucleic Acids Res. 1990 Jun 25;18(12):3587-96 PMID: 2194165
  32. FLICE/caspase-8 activation triggers anoikis induced by beta1-integrin blockade in human keratinocytes.
    J Cell Sci. 2004 Nov 15;117(Pt 24):5815-23 PMID: 15507484
  33. The clinical importance of the nomenclature, evolution and taxonomy of human papillomaviruses.
    J Clin Virol. 2005 Mar;32 Suppl 1:S1-6 PMID: 15753006
  34. Binding of human papillomavirus 16 E6 to p53 and E6AP is impaired by monoclonal antibodies directed against the second zinc-binding domain of E6.
    J Gen Virol. 2005 Apr;86(Pt 4):1001-7 PMID: 15784893
  35. Diversifying selection in human papillomavirus type 16 lineages based on complete genome analyses.
    J Virol. 2005 Jun;79(11):7014-23 PMID: 15890941
  36. HPV 16 E6 sequence variations in Indian patients with cervical neoplasia.
    Cancer Lett. 2005 Nov 8;229(1):93-9 PMID: 15939534
  37. Genome variation of human papillomavirus types: phylogenetic and medical implications.
    Int J Cancer. 2006 Mar 1;118(5):1071-6 PMID: 16331617
  38. Increased risk for cervical disease progression of French women infected with the human papillomavirus type 16 E6-350G variant.
    Cancer Epidemiol Biomarkers Prev. 2006 Apr;15(4):820-2 PMID: 16614130
  39. Cross-regulation between Notch and p63 in keratinocyte commitment to differentiation.
    Genes Dev. 2006 Apr 15;20(8):1028-42 PMID: 16618808
  40. HPV16 E6 natural variants exhibit different activities in functional assays relevant to the carcinogenic potential of E6.
    Virology. 2006 Jun 20;350(1):216-27 PMID: 16519914
  41. Molecular mechanisms of hyperplasia induction by human papillomavirus E7.
    Oncogene. 2006 Jul 13;25(30):4155-64 PMID: 16501608
  42. Human papillomaviruses and cervical cancer.
    Adv Virus Res. 2006;66:125-59 PMID: 16877060
  43. Human papillomavirus type 16 and 18 variants: race-related distribution and persistence.
    J Natl Cancer Inst. 2006 Aug 2;98(15):1045-52 PMID: 16882941
  44. Accelerated degradation of FADD and procaspase 8 in cells expressing human papilloma virus 16 E6 impairs TRAIL-mediated apoptosis.
    Cell Death Differ. 2006 Nov;13(11):1915-26 PMID: 16528386
  45. Modelling the human epidermis in vitro: tools for basic and applied research.
    Arch Dermatol Res. 2007 Jan;298(8):361-9 PMID: 17072628
  46. High grade cervical lesions are caused preferentially by non-European variants of HPVs 16 and 18.
    Int J Cancer. 2007 Apr 15;120(8):1763-8 PMID: 17230525
  47. The large and small isoforms of human papillomavirus type 16 E6 bind to and differentially affect procaspase 8 stability and activity.
    J Virol. 2007 Apr;81(8):4116-29 PMID: 17267478
  48. Activities of human papillomavirus 16 E6 natural variants in human keratinocytes.
    J Med Virol. 2007 Nov;79(11):1751-60 PMID: 17854024
  49. Mechanisms regulating epithelial stratification.
    Annu Rev Cell Dev Biol. 2007;23:93-113 PMID: 17489688
  50. Human papillomaviruses activate caspases upon epithelial differentiation to induce viral genome amplification.
    Proc Natl Acad Sci U S A. 2007 Dec 4;104(49):19541-6 PMID: 18048335
  51. Human papillomavirus 16 E6, L1, L2 and E2 gene variants in cervical lesion progression.
    Virus Res. 2008 Jan;131(1):106-10 PMID: 17869365
  52. Human endogenous retrovirus (HERV-K) reverse transcriptase as a breast cancer prognostic marker.
    Neoplasia. 2008 Jun;10(6):521-33 PMID: 18516289
  53. Gene expression analysis of interferon kappa in laser capture microdissected cervical epithelium.
    Anal Biochem. 2008 Oct 1;381(1):59-66 PMID: 18601893
  54. Human papillomavirus type 16 E6 amino acid 83 variants enhance E6-mediated MAPK signaling and differentially regulate tumorigenesis by notch signaling and oncogenic Ras.
    J Virol. 2004 Jun;78(11):5934-45 PMID: 15140991
  55. Retention of cell adhesion and growth capability in human cervical cancer cells deprived of cell anchorage.
    Jpn J Cancer Res. 1999 Aug;90(8):867-73 PMID: 10543259
  56. Normal growth and differentiation in a spontaneously immortalized near-diploid human keratinocyte cell line, NIKS.
    J Invest Dermatol. 2000 Mar;114(3):444-55 PMID: 10692102
  57. The human papillomavirus type 16 E7 oncogene is required for the productive stage of the viral life cycle.
    J Virol. 2000 Jul;74(14):6622-31 PMID: 10864676
  58. The epidermal growth factor receptor is required to maintain the proliferative population in the basal compartment of epidermal tumors.
    Cancer Res. 2000 Jul 1;60(13):3328-32 PMID: 10910032
  59. Molecular variants of human papillomavirus types 16 and 18 preferentially associated with cervical neoplasia.
    J Gen Virol. 2000 Dec;81(Pt 12):2959-68 PMID: 11086127
  60. p53 codon 72 polymorphism and various human papillomavirus 16 E6 genotypes are risk factors for cervical cancer development.
    Cancer Res. 2001 Jan 15;61(2):608-11 PMID: 11212257
  61. Human papillomavirus type 16 variants and risk of cervical cancer.
    J Natl Cancer Inst. 2001 Feb 21;93(4):315-8 PMID: 11181779
  62. Functional inactivation of p73, a homolog of p53 tumor suppressor protein, by human papillomavirus E6 proteins.
    Int J Cancer. 2001 Mar 15;91(6):822-7 PMID: 11275986
  63. Asian-American variants of human papillomavirus 16 and risk for cervical cancer: a case-control study.
    J Natl Cancer Inst. 2001 Sep 5;93(17):1325-30 PMID: 11535707
  64. Human papillomavirus 16 E6 polymorphisms in cervical lesions from different European populations and their correlation with human leukocyte antigen class II haplotypes.
    Int J Cancer. 2001 Dec 1;94(5):711-6 PMID: 11745467
  65. The human papillomavirus E6 protein and its contribution to malignant progression.
    Oncogene. 2001 Nov 26;20(54):7874-87 PMID: 11753670
  66. Variants of the long control region and the E6 oncogene in European human papillomavirus type 16 isolates: implications for cervical disease.
    Br J Cancer. 2002 Jan 21;86(2):269-73 PMID: 11870518
  67. Persistent human papillomavirus infection and cervical neoplasia.
    Lancet Oncol. 2002 Jan;3(1):11-6 PMID: 11905599
  68. Serum- and calcium-induced differentiation of human keratinocytes is inhibited by the E6 oncoprotein of human papillomavirus type 16.
    J Virol. 1996 May;70(5):3269-79 PMID: 8627810
  69. Natural variants of the human papillomavirus type 16 E6 protein differ in their abilities to alter keratinocyte differentiation and to induce p53 degradation.
    J Virol. 1996 Oct;70(10):6987-93 PMID: 8794343
  70. Papillomavirus infections--a major cause of human cancers.
    Biochim Biophys Acta. 1996 Oct 9;1288(2):F55-78 PMID: 8876633
Article Info
Journal
Virology
Abbr.
Virology
ISSN
1096-0341
DOI
10.1016/j.virol.2008.09.036
Email
zehbei@tbh.net
Published
2009-01-05
Epub
2008-00-04
Pages
69-77
Language
English
Region
United States
NLM ID
0110674
PMCID
PMC2945146
Subset
IM
Grants
NCI NIH HHS · CA022443 · United States
NCI NIH HHS · R01 CA098428-07 · United States
NCI NIH HHS · P01 CA022443-239002 · United States
NCI NIH HHS · R01 CA098428-03 · United States
NCI NIH HHS · P01 CA022443-219002 · United States
NCI NIH HHS · P01 CA022443-280006 · United States
NCI NIH HHS · P01 CA022443-200006 · United States
NCI NIH HHS · P01 CA022443-24S10006 · United States
NCI NIH HHS · P01 CA022443-220006 · United States
NCI NIH HHS · R01 CA098428-04S1 · United States
NCI NIH HHS · P01 CA022443-24S19002 · United States
NCI NIH HHS · CA98428 · United States
NCI NIH HHS · R01 CA098428-02 · United States
NCI NIH HHS · P01 CA022443-23S19002 · United States
NCI NIH HHS · P01 CA022443-310006 · United States
NCI NIH HHS · P01 CA022443-210006 · United States
NCI NIH HHS · P01 CA022443-270006 · United States
NCI NIH HHS · P01 CA022443-250006 · United States
NCI NIH HHS · P01 CA022443-320006 · United States
NCI NIH HHS · R01 CA098428-05 · United States
NCI NIH HHS · P01 CA022443-209001 · United States
NCI NIH HHS · P01 CA022443-230006 · United States
NCI NIH HHS · P01 CA022443-259002 · United States
NCI NIH HHS · P01 CA022443-290006 · United States
NCI NIH HHS · P01 CA022443-249002 · United States
NCI NIH HHS · P01 CA022443-23S10006 · United States
NCI NIH HHS · R01 CA098428-04 · United States
NCI NIH HHS · P01 CA022443-229002 · United States
NCI NIH HHS · P01 CA022443-300006 · United States
NCI NIH HHS · R01 CA098428-01A1 · United States
NCI NIH HHS · R01 CA098428-06 · United States
NCI NIH HHS · P01 CA022443 · United States
NCI NIH HHS · P01 CA022443-260006 · United States
NCI NIH HHS · R01 CA098428 · United States
NCI NIH HHS · P01 CA022443-240006 · United States
External Links
PubMed source DOI: 10.1016/j.virol.2008.09.036 PMC Full Text
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: product@genelibs.com

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2