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1.
PLoS Biol ; 16(10): e2005752, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30359362

RESUMO

The complex life cycle of oncogenic human papillomavirus (HPV) initiates in undifferentiated basal epithelial keratinocytes where expression of the E6 and E7 oncogenes is restricted. Upon epithelial differentiation, E6/E7 transcription is increased through unknown mechanisms to drive cellular proliferation required to support virus replication. We report that the chromatin-organising CCCTC-binding factor (CTCF) promotes the formation of a chromatin loop in the HPV genome that epigenetically represses viral enhancer activity controlling E6/E7 expression. CTCF-dependent looping is dependent on the expression of the CTCF-associated Yin Yang 1 (YY1) transcription factor and polycomb repressor complex (PRC) recruitment, resulting in trimethylation of histone H3 at lysine 27. We show that viral oncogene up-regulation during cellular differentiation results from YY1 down-regulation, disruption of viral genome looping, and a loss of epigenetic repression of viral enhancer activity. Our data therefore reveal a key role for CTCF-YY1-dependent looping in the HPV life cycle and identify a regulatory mechanism that could be disrupted in HPV carcinogenesis.


Assuntos
Fator de Ligação a CCCTC/metabolismo , Papillomaviridae/genética , Fator de Transcrição YY1/metabolismo , Fator de Ligação a CCCTC/genética , Diferenciação Celular/genética , Cromatina/fisiologia , Proteínas de Ligação a DNA/genética , Regulação para Baixo , Epigênese Genética/genética , Histonas/genética , Humanos , Regiões Promotoras Genéticas/genética , Proteínas Repressoras , Fatores de Transcrição , Ativação Transcricional/genética , Replicação Viral/genética , Replicação Viral/fisiologia , Fator de Transcrição YY1/genética
2.
J Invest Dermatol ; 137(10): 2208-2216, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28595997

RESUMO

ß-Human papillomaviruses (HPVs) cause near ubiquitous latent skin infection within long-lived hair follicle (HF) keratinocyte stem cells. In patients with epidermodysplasia verruciformis, ß-HPV viral replication is associated with skin keratosis and cutaneous squamous cell carcinoma. To determine the role of HF keratinocyte stem cells in ß-HPV-induced skin carcinogenesis, we utilized a transgenic mouse model in which the keratin 14 promoter drives expression of the entire HPV8 early region (HPV8tg). HPV8tg mice developed thicker skin in comparison with wild-type littermates consistent with a hyperproliferative epidermis. HF keratinocyte proliferation was evident within the Lrig1+ keratinocyte stem cell population (69 vs. 55%, P < 0.01, n = 7), and not in the CD34+, LGR5+, and LGR6+ keratinocyte stem cell populations. This was associated with a 2.8-fold expansion in Lrig1+ keratinocytes and 3.8-fold increased colony-forming efficiency. Consistent with this, we observed nuclear p63 expression throughout this population and the HF infundibulum and adjoining interfollicular epidermis, associated with a switch from p63 transcriptional activation isoforms to ΔNp63 isoforms in HPV8tg skin. Epidermodysplasia verruciformis keratosis and in some cases actinic keratoses demonstrated similar histology associated with ß-HPV reactivation and nuclear p63 expression within the HF infundibulum and perifollicular epidermis. These findings would suggest that ß-HPV field cancerization arises from the HF junctional zone and predispose to squamous cell carcinoma.


Assuntos
Queratinócitos/patologia , Ceratose Actínica/patologia , Glicoproteínas de Membrana/metabolismo , Neoplasias Experimentais , Células-Tronco Neoplásicas/patologia , Proteínas do Tecido Nervoso/metabolismo , Neoplasias Cutâneas/patologia , Animais , Proliferação de Células , Queratinócitos/metabolismo , Ceratose Actínica/metabolismo , Camundongos , Camundongos Transgênicos , Células-Tronco Neoplásicas/metabolismo , Papillomaviridae , Neoplasias Cutâneas/metabolismo
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