scholarly journals NFX1 Interacts with mSin3A/Histone Deacetylase To Repress hTERT Transcription in Keratinocytes

2008 ◽  
Vol 28 (15) ◽  
pp. 4819-4828 ◽  
Author(s):  
Mei Xu ◽  
Weifeng Luo ◽  
David J. Elzi ◽  
Carla Grandori ◽  
Denise A. Galloway
Keyword(s):  
Human Papillomavirus ◽  
Histone Deacetylase ◽  
Ubiquitin Ligase ◽  
Chromatin Structure ◽  
Hairpin Rna ◽  
Hpv16 E6 ◽  
Human Papillomavirus Type 16 ◽  
Corepressor Complex ◽  
Htert Transcription ◽  
Short Hairpin

ABSTRACT Transcription of the catalytic subunit of telomerase (hTERT) in keratinocytes can be induced by human papillomavirus type 16 (HPV16) E6/E6AP ubiquitin ligase through degradation of the repressor, NFX1-91. Here, we demonstrate that NFX1-91 interacts with the corepressor complex mSin3A/histone deacetylase (HDAC) at the hTERT promoter. By degrading NFX1-91, E6/E6AP changes the chromatin structure at the hTERT promoter as indicated by enhanced acetylation of histones H3 and H4 as well as dimethylation of H3K4. Knockdown of NFX1-91 by short hairpin RNA (shRNA) mimics the effect of E6 and leads to acetylation of histones H3 and H4. Conversely, knockdown of E6AP by shRNA suppresses histone acetylation at the hTERT promoter. These data demonstrate that targeted degradation of NFX1-91 by E6/E6AP dissociates the mSin3A/HDAC complex from the hTERT promoter and induces hTERT transcription.

scholarly journals MicroRNA 203 Expression in Keratinocytes Is Dependent on Regulation of p53 Levels by E6

2010 ◽  
Vol 84 (20) ◽  
pp. 10644-10652 ◽  
Author(s):  
Declan J. McKenna ◽  
Simon S. McDade ◽  
Daksha Patel ◽  
Dennis J. McCance
Keyword(s):  
Dna Damage ◽  
Human Papillomavirus ◽  
Cell Biology ◽  
Viral Oncoprotein ◽  
Hpv16 E6 ◽  
Human Papillomavirus Type 16 ◽  
Proliferation And Differentiation ◽  
Short Hairpin ◽  
E6 And E7 ◽  
Short Hairpin Rnas

ABSTRACT A screen of microRNA (miRNA) expression following differentiation in human foreskin keratinocytes (HFKs) identified changes in several miRNAs, including miRNA 203 (miR-203), which has previously been shown to play an important role in epithelial cell biology by regulating p63 levels. We investigated how expression of human papillomavirus type 16 (HPV16) oncoproteins E6 and E7 affected miR-203 expression during proliferation and differentiation of HFKs. We demonstrated that miR-203 expression is reduced in HFKs where p53 function is compromised, either by the viral oncoprotein E6 or by knockout of p53 using short hairpin RNAs (p53i). We show that the induction of miR-203 observed during calcium-induced differentiation of HFKs is significantly reduced in HFKs expressing E6 and in p53i HFKs. Induction of miR-203 in response to DNA damage is also reduced in the absence of p53. We report that proliferation of HFKs is dependent on the level of miR-203 expression and that overexpression of miR-203 can reduce overproliferation in E6/E7-expressing and p53i HFKs. In summary, these results indicate that expression of miR-203 is dependent on p53, which may explain how expression of HPV16 E6 can disrupt the balance between proliferation and differentiation, as well as the response to DNA damage, in keratinocytes.

Retrovirus-mediated delivery of short hairpin RNA targeting human papillomavirus (HPV) 16 E6 and E7 oncogenes and induction of apoptosis in oropharyngeal squamous cell cancer (OSCC) cell line

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 6002-6002 ◽  
Author(s):  
T. Rampias ◽  
C. Sasaki ◽  
D. DiMaio ◽  
A. Psyrri
Keyword(s):  
Gene Therapy ◽  
Human Papillomavirus ◽  
Cell Cancer ◽  
Short Hairpin Rna ◽  
Mrna Levels ◽  
Rt Pcr ◽  
Hairpin Rna ◽  
Hpv16 E6 ◽  
Short Hairpin ◽  
E6 And E7

6002 Background: Human papillomavirus type 16 is identified in almost 50% of the cases of OSCC. The E6 and E7 genes of HPVs encode oncoproteins that bind and degrade the tumor suppressor proteins p53 and Rb, respectively. We are exploring the potential use of short hairpin RNA (sh RNA) for gene therapy of HPV-positive OSCC. Methods: Small hairpin RNAs targeting E6 or E7 genes were delivered by a retrovirus vector to 93VU147T (bearing integrated HPV16 DNA) and 92VU040T (HPV negative) oropharyngeal cancer cell lines. Flow cytometry analysis was used to assess apoptosis after the retrovirus infection. The E6 and E7 mRNA downregulation was assessed by reverse transcription polymerase chain reaction (RT-PCR). At protein level p53 and Rb expression were evaluated with Western blotting analysis. Results: Apoptosis was seen in over 90% of 93VU147T cells 48 hours after infection whereas 92VU040T cells were not affected. RT-PCR demonstrated that HPV16 E6/E7 mRNA levels decreased significantly in infected 93VU147T cells. 93VU147T infected cells also showed a marked increase in p53 and Rb protein levels. Conclusions: Downregulation of E6/E7 gene expression in HPV16+ OSCC cells results in apoptosis and reactivation of p53 and Rb tumor suppression pathways. These results have significant implications in treating HPV-associated OSCC with HPV-targeted gene therapy. No significant financial relationships to disclose.

scholarly journals Identification and characterization of enhancer agonist human cytotoxic T-cell epitopes of the human papillomavirus type 16 (HPV16) E6/E7

Vaccine ◽  
2017 ◽  
Vol 35 (19) ◽  
pp. 2605-2611 ◽  
Author(s):  
Kwong Y. Tsang ◽  
Massimo Fantini ◽  
Romaine I. Fernando ◽  
Claudia Palena ◽  
Justin M. David ◽  
...  
Keyword(s):  
Human Papillomavirus ◽  
T Cell ◽  
Cytotoxic T Cell ◽  
T Cell Epitopes ◽  
Hpv16 E6 ◽  
Human Papillomavirus Type 16 ◽  
Identification And Characterization

scholarly journals CHD8 Is an ATP-Dependent Chromatin Remodeling Factor That Regulates β-Catenin Target Genes

2008 ◽  
Vol 28 (12) ◽  
pp. 3894-3904 ◽  
Author(s):  
Brandi A. Thompson ◽  
Véronique Tremblay ◽  
Grace Lin ◽  
Daniel A. Bochar
Keyword(s):  
Gene Expression ◽  
Rna Interference ◽  
Chromatin Remodeling ◽  
Gene Transcription ◽  
Chromatin Structure ◽  
Target Genes ◽  
Promoter Regions ◽  
Hairpin Rna ◽  
Short Hairpin ◽  
Targeted Gene Expression

ABSTRACT ATP-dependent chromatin remodeling by the CHD family of proteins plays an important role in the regulation of gene transcription. Here we report that full-length CHD8 interacts directly with β-catenin and that CHD8 is also recruited specifically to the promoter regions of several β-catenin-responsive genes. Our results indicate that CHD8 negatively regulates β-catenin-targeted gene expression, since short hairpin RNA against CHD8 results in the activation of several β-catenin target genes. This regulation is also conserved through evolution; RNA interference against kismet, the apparent Drosophila ortholog of CHD8, results in a similar activation of β-catenin target genes. We also report the first demonstration of chromatin remodeling activity for a member of the CHD6-9 family of proteins, suggesting that CHD8 functions in transcription through the ATP-dependent modulation of chromatin structure.

scholarly journals The High-Risk Human Papillomavirus Type 16 E6 Counters the GAP Function of E6TP1 toward Small Rap G Proteins

2003 ◽  
Vol 77 (2) ◽  
pp. 1614-1620 ◽  
Author(s):  
Latika Singh ◽  
Qingshen Gao ◽  
Ajay Kumar ◽  
Takaya Gotoh ◽  
David E. Wazer ◽  
...  
Keyword(s):  
Human Papillomavirus ◽  
High Risk ◽  
G Protein ◽  
Mutational Analysis ◽  
Protein Signaling ◽  
Hpv16 E6 ◽  
Human Papillomavirus Type 16 ◽  
Hpv E6 ◽  
Small G Protein ◽  
Transforming Activity

ABSTRACT We have recently identified E6TP1 (E6-targeted protein 1) as a novel high-risk human papillomavirus type 16 (HPV16) E6-binding protein. Importantly, mutational analysis of E6 revealed a strong correlation between the transforming activity and its abilities to bind and target E6TP1 for ubiquitin-mediated degradation. As a region within E6TP1 has high homology with GAP domains of known and putative Rap GTPase-activating proteins (GAPs), these results raised the possibility that HPV E6 may alter the Rap small-G-protein signaling pathway. Using two different approaches, we now demonstrate that human E6TP1 exhibits GAP activity for Rap1 and Rap2, confirming recent findings that a closely related rat homologue exhibits Rap-specific GAP activity. Using mutational analysis, we localize the GAP activity to residues 240 to 945 of E6TP1. Significantly, we demonstrate that coexpression of HPV16 E6, by promoting the degradation of E6TP1, enhances the GTP loading of Rap. These results support a role of Rap small-G-protein pathway in E6-mediated oncogenesis.

scholarly journals Analysis of mutations in the E6/E7 oncogenes and L1 gene of human papillomavirus 16 cervical cancer isolates from China

2006 ◽  
Vol 87 (5) ◽  
pp. 1181-1188 ◽  
Author(s):  
Yuping Wu ◽  
Yulong Chen ◽  
Longyu Li ◽  
Guifang Yu ◽  
Ying He ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Human Papillomavirus ◽  
Cancer Patients ◽  
Hpv Infection ◽  
Typing Method ◽  
Hpv16 E6 ◽  
Human Papillomavirus 16 ◽  
Human Papillomavirus Type 16 ◽  
New Variant

Human papillomavirus type 16 (HPV16) has a number of intratypic variants; each has a different geographical distribution and some are associated with enhanced oncogenic potential. Cervical samples were collected from 223 cervical cancer patients and from 196 age-matched control subjects in China. DNA samples were amplified by using primers specific for the E6, E7 and partial L1 regions. Products were sequenced and analysed. It was found by using a PCR–sequence-based typing method that HPV infection rates in China were 92·8 % in cervical cancer patients and 15·8 % in healthy controls. HPV16 was detected in 70·4 % of cervical cancer patients and in 6·1 % of controls. In HPV16-positive cervical cancers, 23·6 % belonged to the prototype, 65·5 % were of the Asian variant, 5·5 % were of African type 1 and 3·6 % were European variants, whilst only one was a new variant that differed from any variant published so far. Prevalences of HPV16 E6 D25E and E113D variants were 67·3 and 9 %, respectively. In addition to D25E and E113D, the following E6 variations were found in this study: R129K, E89Q, S138C, H78Y, L83V and F69L. The results also showed that the prevalences of three hot spots of E7 nucleotide variation, N29S, S63F and a silent variation, nt T846C, were 70·2 % (33/47), 51·1 % (24/47) and 61·7 % (29/47), respectively. The following L1 variations were found in this study: S377A, K387E, E378D, K382E and T379P. It was also found that the average age of Asian variant-positive cervical cancer patients (42·98±10·43 years) was 7·56 years lower than that of prototype-positive patients (50·54±10·91). It is suggested that the high frequency of HPV16 Asian variants might contribute to the high incidence of cervical cancer in China.

scholarly journals p53 Is Regulated in a Biphasic Manner in Hypoxic Human Papillomavirus Type 16 (HPV16)-Positive Cervical Cancer Cells

2020 ◽  
Vol 21 (24) ◽  
pp. 9533
Author(s):  
Linhan Zhuang ◽  
Regina Ly ◽  
Frank Rösl ◽  
Martina Niebler
Keyword(s):  
Human Papillomavirus ◽  
Cancer Cells ◽  
Dynamic Regulation ◽  
Cellular Adaptation ◽  
Hpv16 E6 ◽  
Human Papillomavirus Type 16 ◽  
Hypoxic Conditions ◽  
Cervical Cancer Cells ◽  
Adaptation Processes ◽  
The Impact

Although the effect of hypoxia on p53 in human papillomavirus (HPV)-positive cancer cells has been studied for decades, the impact of p53 regulation on downstream targets and cellular adaptation processes during different periods under hypoxia remains elusive. Here, we show that, despite continuous repression of HPV16 E6/E7 oncogenes, p53 did not instantly recover but instead showed a biphasic regulation marked by further depletion within 24 h followed by an increase at 72 h. Of note, during E6/E7 oncogene suppression, lysosomal degradation antagonizes p53 reconstitution. Consequently, the transcription of p53 responsive genes associated with senescence (e.g., PML and YPEL3) cannot be upregulated. In contrast, downstream genes involved in autophagy (e.g., DRAM1 and BNIP3) were activated, allowing the evasion of senescence under hypoxic conditions. Hence, dynamic regulation of p53 along with its downstream network of responsive genes favors cellular adaptation and enhances cell survival, although the expression of the viral E6/E7-oncogenes as drivers for proliferation remained inhibited under hypoxia.

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