Activities of E7 promoters in the human papillomavirus type 16 genome during cell differentiation

Hansen, Christina; Nielsen, Lone; Norrild, Bodil

doi:10.1016/j.virusres.2010.02.009

Cited by 9 publications

(10 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Consistent with this, it has been reported that in productive papillomavirus infection, and also in low-grade squamous intraepithelial lesions, the presence of E7 and of surrogate markers of E7 is absent or diminished in the upper cell layers compared to the basal and suprabasal layers (22,(82)(83)(84), probably resulting from reduced P97 activity. In line with this, it has been shown that in differentiated SiHa cells, mimicking the upper tissue cell layers where we detected TBX2 and L2, P97 activity is inhibited (85). This could be the result of an increase in TBX2 levels during differentiation of SiHa cells, similar to our observation that TBX2 is accumulated in the differentiated upper cell layers.…”

Section: Discussionsupporting

confidence: 91%

The Transcription Factors TBX2 and TBX3 Interact with Human Papillomavirus 16 (HPV16) L2 and Repress the Long Control Region of HPVs

Schneider

Scheffer

Bund

et al. 2013

J Virol

View full text Add to dashboard Cite

The minor capsid protein L2 of human papillomaviruses (HPVs) has multiple functions during the viral life cycle. Although L2 is required for effective invasion and morphogenesis, only a few cellular interaction partners are known so far. Using yeast twohybrid screening, we identified the transcription factor TBX2 as a novel interaction partner of HPV type 16 (HPV16) L2. Coimmunoprecipitations and immunofluorescence analyses confirmed the L2-TBX2 interaction and revealed that L2 also interacts with TBX3, another member of the T-box family. Transcription of the early genes during HPV infection is under the control of an upstream enhancer and early promoter region, the long control region (LCR). In promoter-reporter gene assays, we observed that TBX2 and TBX3 repress transcription from the LCR and that this effect is enhanced by L2. Repression of the HPV LCR by TBX2/3 seems to be a conserved mechanism, as it was also observed with the LCRs of different HPV types. Finally, interaction of TBX2 with the LCR was detected by chromatin immunoprecipitation, and we found a strong colocalization of L2 and TBX2 in HPV16-positive cervical intraepithelial neoplasia (CIN) I-II tissue sections. These results suggest that TBX2/3 might play a role in the regulation of HPV gene expression during the viral life cycle. Human papillomaviruses (HPVs) are small, nonenveloped viruses that infect stratified squamous epithelia of the skin or mucous membranes, inducing a variety of hyperproliferative lesions (1). The mucosotropic HPVs are classified as either low-risk or high-risk types. Lesions resulting from high-risk HPV infections (e.g., HPV type 16 [HPV16], HPV18, and HPV31) can progress to cervical and other cancers (2, 3). The icosahedral capsid of HPVs consists of 360 copies of the major capsid protein L1 (4, 5) and up to 72 copies of the minor capsid protein L2 (6). During HPV infection, L2 is required for the egress of the viral genome from endosomes (7) and for the dynein-mediated transport of the viral genome along microtubules to the nucleus (8-10). In the final steps of viral entry, L2 chaperones the viral genome to nuclear domain 10 (ND10), where initial transcription of the viral genes takes place (11). Transcription of the early viral proteins E6 and E7, representing the transforming oncogenes in high-risk HPVs, is controlled by an upstream enhancer sequence, the long control region (LCR) (also called the upstream regulatory region [URR]), which comprises the early promoter. A complex array of cellular and viral factors binds to the LCR and regulates expression of the early viral genes (12-21). The composition of the factors binding and regulating the LCR is dependent on differentiation of the host keratinocytes (22,23). In the granular cell layers, the activation of the late promoter drives the expression of the capsid proteins L1 and L2 (24-26). Besides its importance in viral entry, L2 plays a major role during virus morphogenesis. L2 reorganizes ND10 protein composition and recruits L1 into these subnuclear structures, ...

show abstract

Section: Discussionsupporting

confidence: 91%

The Transcription Factors TBX2 and TBX3 Interact with Human Papillomavirus 16 (HPV16) L2 and Repress the Long Control Region of HPVs

Schneider

Scheffer

Bund

et al. 2013

J Virol

View full text Add to dashboard Cite

show abstract

“…However, the oncogene expression may be maintained, although at a lower level, by p441 and p542-promoter expression in cases in which p97 downregulation is induced by added high levels of calcium as stated by Hansen et al. 28 . Contradictory to these reports, our results showed that the calcium switch eventually lead to increased E6 transcription as the difference in the mRNA levels was not apparent before the day 9 in a high-calcium medium (Fig.…”

Section: Discussionmentioning

confidence: 92%

“…4 ). Hansen and coworkers 28 analysed their samples at day 5, not necessarily allowing enough time for the late effects of calcium to completely manifest. This is also supported by the work of Deyrieux and Wilson 29 who reported that calcium-induced differentiation occurred in 144 h after switching the calcium concentration.…”

Section: Discussionmentioning

confidence: 99%

Extracellular calcium regulates keratinocyte proliferation and HPV 16 E6 RNA expression in vitro

Turunen

Syrjänen

2014

APMIS

View full text Add to dashboard Cite

Human papillomaviruses (HPV) are known to immortalize oral keratinocytes in vitro, but the underlying mechanisms causing the following resistance to differentiation remain unclear. We investigated the effect of extracellular calcium on the proliferation of HPV16-positive keratinocytes and on the mRNA expression of the viral E6-oncogene. HPV16-positive hypopharyngeal carcinoma cells (UD-SCC-2), spontaneously immortalized- (HMK) and HPV16 E6/E7-immortalized human gingival keratinocytes (IHGK) were grown for 3, 6 and 9 days in Keratinocyte Serum-free Medium with calcium concentrations ranging from 0 mM to 6 mM. Calcium concentrations up to 0.09 mM increased cellular proliferation, which decreased at higher concentrations. A shift of calcium concentration from 0 to 4 mM increased E6 expression in UD-SCC-2 cells 2.4-fold by day 9. Simultaneously, E2 expression increased. The most significant upregulation of E6 and E2 expressions was observed at day 9, grown in high-calcium media and the increase in E6 expression coincided with an increase in involucrin expression, likely indicating cell differentiation. Despite this, HPV-positive cells continued to proliferate even at high-calcium media in contrast to HPV-negative cells. Overexpression of E6 mRNA may be an important feature of HPV16-positive cells to resist the natural calcium gradient in differentiating keratinocytes allowing cell proliferation.

show abstract

“…Several other promoters which might play an important role in the viral life cycle have been identified [9][10][11][12][13]. Transcription of HPV late genes is only activated as HPVpositive cells start to differentiate [14,15].…”

Section: Regulation Of Transcriptionmentioning

confidence: 99%

Human papillomavirus gene expression is controlled by host cell splicing factors

Klymenko

Graham

2012

Biochemical Society Transactions

View full text Add to dashboard Cite

HPVs (human papillomaviruses) infect stratified epithelia and cause a variety of lesions ranging from benign warts to invasive tumours. The virus life cycle is tightly linked to differentiation of the keratinocyte it infects: papillomaviruses modulate host gene expression to ensure efficient virus replication. For example, the viral transcription factor E2 can directly up-regulate, in an epithelial differentiation-dependent manner, cellular SRSFs [SR (serine/arginine-rich) splicing factors] that control constitutive and alternative splicing. Changes in alternative splicing and the mechanisms controlling this for viral mRNAs have been the subject of intense exploration. However, to date experiments have only been carried out in model systems because the genetic systems suitable for studying alternative splicing of viral RNAs in the context of the virus life cycle are relatively recent and technically challenging. Now using these life cycle-supporting systems, our laboratory has identified SR proteins as important players in differentiation-dependent regulation of HPV gene expression. Better understanding of the role of cellular factors in regulating the virus life cycle is needed as it may help development of novel diagnostic approaches and antiviral therapies in the future.

show abstract

Activities of E7 promoters in the human papillomavirus type 16 genome during cell differentiation

Cited by 9 publications

References 41 publications

The Transcription Factors TBX2 and TBX3 Interact with Human Papillomavirus 16 (HPV16) L2 and Repress the Long Control Region of HPVs

The Transcription Factors TBX2 and TBX3 Interact with Human Papillomavirus 16 (HPV16) L2 and Repress the Long Control Region of HPVs

Extracellular calcium regulates keratinocyte proliferation and HPV 16 E6 RNA expression in vitro

Human papillomavirus gene expression is controlled by host cell splicing factors

Contact Info

Product

Resources

About