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We are in the midst of a global turn to the drone. Responding to the ‘unmanning’ of contemporary warfare, interdisciplinary scholarship has interrogated the human operators and non-human actors underpinning the drone, and their wide-ranging ethical, geopolitical, and legal implications. A key facet of extant drone debates surrounds drone vision – both as it operationally visualizes and is fetishized. While comparatively nascent, scholars have begun to explore how drones are instead visualized across particular media. In this article I identify two lacuna within extant drone scholarship: first a lack of attentiveness to small military drones, which while comprising the majority of global military arsenals remain comparatively absent from scholarly analysis; and second, a need to attend to a greater diversity of visual representations of the drone. In response, this article explores promotional visualizations of small military drones as they are ethnographically-encountered at a key site through which their usage is compelled and their functioning enabled – the defence tradeshow. In so doing, I identify three central frames through which the drone is repeatedly represented therein. I argue that these frames both engage and employ visual conventions associated with ‘nature’ and the ‘natural’ in order to ‘naturalize’ and normalize the drone in as-yet unaccounted ways. Approaching the drone through the current, yet under-examined, visual milieu of the defence environments in which it is promoted, the article contributes to both interdisciplinary drone scholarship, and literatures exploring the visual cultures of militarism more widely.

As drones have emerged as icons of contemporary warfare so too have drone operators become symbols of contemporary warfighting. While drone scholarship to date has predominantly centred upon exploring the drone’s “functioning” and “implications”, including interrogating the ‘in-theatre’ experiences of operators, this article responds to calls for further attentiveness to the “making of” the drone (Klauser and Pedrozo in Geogr Helv 70:285-293, 2015). In empirically examining the ‘making of’ the drone operator, it turns to their training, and in particular the use of simulators therein. This focus, it argues, offers an alternative accounting of the drone operator, one that both revisits and complicates existing and enduring narratives of drone operation and/as videogaming, and one that offers an alternative temporality and ‘site’ through which to explore how drones come to ‘function’.

The last two decades have seen a “volumetric turn” within Anglophone social sciences and humanities scholarship. This turn is premised on the idea that space may be better understood in three-dimensional terms – with complex heights and depths – rather than as a series of two-dimensional areas or surfaces. While there is an increasingly diverse and rich set of scholarship accounting for voluminous complexities in the air, oceans, ice, mountains, and undergrounds, all too often this work foregrounds state and military-led approaches to volume. This has resulted in a limited methodological toolkit through which to explore voluminous complexities as they emerge and extend beyond military and state contexts. Often reliant on elite interviews, archives, and cartographies, there has been little critical discussion of both methodological practice and the “flatness” of research outputs articulating three-dimensional worlds. In this paper we address this by foregrounding the role of immersive and multisensory methodologies (sounding volumes, seeing-sensing drone volumes, and object volumes). To conclude, we offer avenues for further inquiry, including attending to shifting everyday voluminous experiences in the Anthropocene, and the need to diversify the communication of “volume” research.

We live in an increasingly drone-saturated world. In this article, we bring drone scholarship and feminist geopolitics into dialogue to interrogate the drone-home. We re-orient military- and state-led accounts, foregrounding the growing range of non-state actors enacting and subject to the drone as it is increasingly employed in the Global North. In so doing, we develop the concept of ‘everyday droning’ as the honing and homing of military technology and drone capitalism. Examining militarization and enclosure at the scale of everyday home life, we urge future geographical work to engage with everyday droning being actively seeded in the domestic here-and-now.

While the drone has become synonymous with the War on Terror, the asymmetric iconography of the battlefield is shifting. Commercially available off-the-shelf (COTS) drones are increasingly prevalen...

In ‘Aerial aftermaths: wartime from above’, Caren Kaplan revisits, and crucially re-narrates, the aerial gaze. Interrogating aerial technologies and techniques through the lens of the ‘aftermath’, ...

Drones are increasingly understood and imagined as important actors, inhabiting and transforming aerial space. From their entrenched establishment within battlefield operations, drones have spawned into a diverse ecosystem of platforms and applications, increasingly punctuating domestic urban airspace. While occupying a status as exemplars of urban innovation, the drone poses, and remains bound to, a range of techno-cultural contestations – from challenges around airspace integration, to concerns around privacy, safety and pollution. Thinking with commercial drone futures, and specifically the logistics sector, this article interrogates the role of speculation in this unfolding techno-landscape. In so doing we turn to two key sites through which the drone is anticipated – namely patents and adverts – as lenses through which to investigate projected visualisations underpinning the emergent, envisioned and anticipated drone. We argue that such drone speculations do not simply and solely envision new means of circulating goods, people and information, but rather embody and act to promote a particular set of aerial desires and social relations. Critically unpacking envisioned notions of frictionless mobility, instant consumption, and the appropriation of vertical spaces and spectra, we argue that such speculative sites and practices importantly participate in a techno-fetishist agenda positing drone technology as a privileged and panacea agent of futurity, while often eliding its implications.

The constructs of ‘territory’ and ‘terrain’ are the subject of increasing scrutiny within political geography. While momentum builds in their interrogation as both diverse and lively practices, and complex political technologies, this article takes pause. Drawing on a rich and diverse range of feminist scholarship, it seeks to reflect upon existing trajectories and provide provocation for further accounting. Inspired throughout by, and seeking to bring to bear, a feminist perspective on territory and terrain, this article follows a tripartite structure. First, it critically explores the bodies of knowledge historically underpinning the concepts of territory and terrain. Developing a call for a feminist historiography of territory and terrain, we reflect upon both the gendered evolution of the concepts, and their ongoing reproduction in conceptual debates. Second, it seeks to both highlight and diversify embodied accounts and accountings of these concepts. Here, thinking with and beyond the body, we turn to the non-human and spiritual to explore territory and terrain in expanded and extended ways. Lastly, we examine bodies of expertise, reflecting on academic territories and terrains, and highlighting potential concepts and methodologies seeking to (re-)sculpt and (re-)articulate understandings of territory and terrain. The paper, whilst not all-encompassing, serves as an important provocation that seeks more equitable accounts of political geography's messy, muddy, and lively territories and terrains.

Drones have been posited as the "signature device of the present moment" (Noys, 2014). Whilst research into the proliferation of drones in military and defence spheres is gaining notable momentum, drones in commercial and "civilian" contexts "have remained widely unnoticed in academic research" (Klauser and Pedrozo, 2015:285). Complementing emergent scholarship in this area, this paper seeks to both explore and assert the trade show as a valuable site of (industry and advocacy) community "copresence" (McCann, 2011). Drawing upon empirical data, this paper unpacks the rhetorical framing of the commercial drone in the trade-show environment. In so doing, it explores two dominant rhetorical framings, or "techniques of imagination" (Kinsley, 2012:1559), of the commercial drone: those of possibility and inevitability. Such an analysis seeks to respond to calls advocating further attention to the "making of the drone", prior to its "functioning" (Klauser and Pedrozo, 2015) and end-point applications.

3-D cinema is a largely overlooked media within geographical critique. This omission is notable given both the sustained academic consideration afforded to other popular media, the medium’s significant commercial and popular success, and its status as an ‘affective’ and captivating storytelling medium. With reference to film industry advertisements, the experiential dimensions of the 3-D cinematic encounter and its (popular) framing as an ‘immersive’ consumer experience are explored. In particular, the notion of ‘immersion’ is unpacked with reference to the medium’s engineering and production techniques. In so doing, the intertwinement of the industrial desire for ever more ‘immersive’ and ‘realistic’ consumer experience is explored in relation to the engineering techniques exhibiting perceptual mimicry, or what could be termed ‘mimetic engineering’. The association between 3-D cinema and ‘tactile’ images is then explored with reference to geographic literatures on ‘haptics’ and technologies of touch. A number of recent ‘innovations’ in these fields are drawn upon in order to complicate 3-D cinema’s association with ‘tactility’. In so doing, a technological shift towards the increasingly pervasive and sophisticated engagement of the wider multi-sensory palette is explored. Drawing upon recent media technology ‘innovations’, this persistent and relentless desire for ever more ‘immersive’ and perceptually-convincing media technology is explored in light of developing media geographies.

We recently showed that E6 protein of human papillomavirus (HPV) 16, a mucosal high-risk α-PV type, can potentiate Wnt/β-catenin/TCF signaling. Here we investigated the transcriptional activities of E6 proteins of cutaneous HPV types from the β and α genera. Results from reporter-gene assays showed that similar to HPV16 E6, E6 of HPV10, a cutaneous α-HPV type that is prevalent in skin warts, efficiently enhances and stimulates Wnt/β-catenin/TCF transcription. HPV10 E6 also effectively elevated the expression levels of β-catenin and promoted its nuclear accumulation. E6 proteins of β-HPV types 8, 24, 38 and 49, which are prevalent in skin cancer, exhibited lower activities in all tested functions. The differences in activity correlated with E6's competence to interact with the ubiquitin ligase E6AP. This study reveals a role for E6 proteins of diverse cutaneous HPV types in potentiation of Wnt/β-catenin signaling, irrespective of their carcinogenic potential.

The present study investigated the roles of E6 and E6AP in the Wnt pathway. We showed that E6 levels are markedly reduced in cells in which Wnt signaling is activated. Coexpression of wild-type or mutant E6AP (C820A) in Wnt-activated cells stabilized E6 and enhanced Wnt/β-catenin/TCF transcription. Expression of E6AP alone in nonstimulated cells elevated β-catenin level, promoted its nuclear accumulation, and activated β-catenin/TCF transcription. A knockdown of E6AP lowered β-catenin levels. Coexpression with E6 intensified the activities of E6AP. Further experiments proved that E6AP/E6 stabilize β-catenin by protecting it from proteasomal degradation. This function was dependent on the catalytic activity of E6AP, the kinase activity of GSK3β and the susceptibility of β-catenin to GSK3β phosphorylation. Thus, this study identified E6AP as a novel regulator of the Wnt signaling pathway, capable of cooperating with E6 in stimulating or augmenting Wnt/β-catenin signaling, thereby possibly contributing to HPV carcinogenesis.

The Ashgate Research Companion to Critical Geopolitics provides an insightful overview of the sub-discipline of critical geopolitics. The collection encompasses a critical interrogation of the sub-...

Recently, we showed that the ubiquitin ligase E6AP stabilizes β-catenin and activates its transcriptional activity. These activities were enhanced by the human papillomavirus (HPV) E6 protein. In the present study, we explored the function of E6AP, which increases β-catenin stabilization and transcriptional activation. Here, we report that E6AP interacts with β-catenin and mediates its nonproteolytic ubiquitylation, as evidenced in transiently transfected cell-based and in vitro reconstitution ubiquitylation assays. Overexpression of E6AP increased β-catenin polyubiquitylation and, consistent with that, knockdown or knock-out of E6AP expression reduced β-catenin polyubiquitylation. The ubiquitylation of β-catenin by E6AP was dependent on its E3 ubiquitin ligase activity, but it was proteasome-independent and did not require HPV-E6, phosphorylation of β-catenin by glycogen synthase kinase 3β (GSK3β) or activity of the β-catenin ‘destruction complex’. We also show that transcriptional activation of β-catenin by E6AP is coupled with β-catenin protein stabilization, but not its ubiquitylation. In contrast to β-catenin ubiquitylation, β-catenin protein stability and its transcriptional activity were absolutely dependent on the activity of the destruction complex and phosphorylation by GSK3β. Collectively, our data uncover a dual role for E6AP in the regulation of β-catenin ubiquitylation, stability and transcriptional activity, with HPV-E6 enhancing only part of E6AP activities.

Current therapies for treatment of advanced cervical cancer involve the use of cisplatin, often in combination with radiotherapy. These treatments do not lead to a high survival rate and furthermore, serious side effects are dose-limiting factors. Methyl jasmonate (MJ) was recently identified as potent and selective cytotoxic agent towards cervical cancer cells. In the present study we evaluated the effectiveness of combined treatments of MJ with cisplatin or X-irradiation on a variety of cervical cancer cells including SiHa, CaSki, HeLa and C33A. Cytotoxicity of alpha particles, emitted from (224)Ra atoms, was also evaluated as a single agent and in combination with MJ. Cooperation between MJ and cisplatin in reducing cell viability (XTT assays) and survival (clonogenicity assays) was exhibited towards several cancer cell lines at a range of combination doses. MJ effectively cooperated also with X-ray irradiation, significantly lowering the radiation doses required to inhibit cell survival (ID50) of all tested cells lines. We show for the first time, that alpha irradiation selectively reduced cell viability and survival of cervical cancer cells. Lower doses of α irradiation were required as compared to X-irradiation to inhibit cell survival. Cooperation with MJ was demonstrated in part of the cancer cell lines. In conclusion, our studies point to α irradiation and MJ, novel anticancer agents, as potent candidates for treatment of cervical cancer, in single agent regiments and in combination. MJ can be added also to conventional X-ray and cisplatin therapies to increase their cytotoxic effect while lowering the effective dose.

In this study we investigated the effect of HPV16 E6 on the Wnt/beta-catenin oncogenic signaling pathway. Luciferase reporter assays indicated that ectopically expressed E6 significantly augmented the Wnt/beta-catenin/TCF-dependent signaling response in a dose-dependent manner. This activity was independent of the ability of E6 to target p53 for degradation or bind to the PDZ-containing E6 targets. Epistasis experiments suggested that the stimulatory effect is independent of GSK3beta or APC. Coexpression, half-life determination, cell fractionation and immunofluorescence analyses indicated that E6 did not alter the expression levels, stability or cellular distribution of beta-catenin. Further experiments using E6 mutants defective for E6AP binding and E6AP knockdown cells indicated the absolute requirement of the ubiquitin ligase E6AP for enhancement of the Wnt signal by E6. Thus, this study suggests a role for the E6/E6AP complex in augmentation of the Wnt signaling pathway which may contribute to HPV induced carcinogenesis.

In the present study the effectiveness of methyl jasmonate (MJ) against cervical cancer cell lines was investigated. We show that MJ is cytotoxic to a range of cervical cancer lines including SiHa, CaSki and HeLa that carry human papillomavirus (HPV) DNA and wild type p53, and C33A that is negative for HPV and contains mutant p53. Primary human foreskin keratinocytes were almost resistant to the drug. Cytotoxicity of MJ was dose and time dependent, and associated mainly with the induction of cell death and to a less extent with inhibition of cell growth. Cell death induced by MJ displayed features characteristic to both apoptosis and necrosis, and was associated with different changes in the levels of p53, p21, bcl-2 and bax in the various cervical cancer lines. In conclusion, MJ a novel anticancer agent, acts via multiple pathways to induce death of cervical cancer cells, thus making it a promising candidate for treatment of cervical cancer.

Previous studies have shown that human papillomavirus (HPV) 16 E6 inhibits apoptosis induced during terminal differentiation of primary human keratinocytes (PHKs) triggered by serum and calcium. E6 inhibition of apoptosis was accompanied with prolonged expression of Bcl-2 and reduced elevation of Bax levels. In the present study, the effect of E6 on Bax mRNA expression and protein stability was investigated. These studies indicate that stable E6 expression in differentiating keratinocytes reduced the steady-state levels of Bax mRNA and shortened the half-life of Bax protein. These results were confirmed in transiently transfected 293T cells where E6 degraded Bax in a dose-dependent manner. Bax degradation was also exhibited in Saos-2 cells that lack p53, indicating its p53 independence. E6 did not form complexes with Bax and did not induce Bax degradation in vitro under experimental conditions where p53 was degraded. Finally, E6 aa 120–132 were shown to be necessary for Bax destabilization and, more importantly, for abrogating the ability of Bax to induce cellular apoptosis, highlighting the functional consequences of the E6-induced alterations in Bax expression.

Transfection of the E6 gene of human papillovirus (HPV) 16 into primary human keratinocytes (PHKs) generates proliferating cell colonies which are resistant to serum- and calcium-induced terminal differentiation. The extreme C-terminus of E6 was shown to be dispensable for this activity. To map further the amino acid sequences required for inducing resistance to serum and calcium, and to address the functional significance of E6 interactions with p53 and E6BP (ERC-55) in this function, we evaluated the activities of a series of E6 mutants. Small deletions within the central portion of the second putative zinc-finger abolished, or markedly reduced, E6 biological activity, while mutations affecting the cysteine residues in the base of the finger were less effective in this respect. When these mutants were assayed for their ability to degrade p53 in vitro and in vivo and to inhibit p53 transcriptional activation (TA), we found that there was a dissociation of these activities in some mutants. We mapped one mutant which was highly efficient in p53 degradation and inhibition of p53 TA, yet displayed severely reduced activity in the biological assay, and conversely, a subset of mutants that showed moderate activities in the colony assay while being severely impaired in p53 degradation and inhibition of p53 TA. These data argue that p53 inactivation or even elimination are not sufficient, and may not be essential, for altering the response of PHKs to serum and calcium. When these E6 mutants were evaluated for E6BP binding in vitro, there was a similar dissociation between the biological and biochemical activities of several mutants. We mapped mutants with moderate activity in the biological assay that lacked the ability to bind to E6BP and a mutant that showed high biological activity with only marginal binding to E6BP. Thus, there is no absolute correlation between the ability of E6 mutant proteins to induce alterations in keratinocyte differentiation responses to calcium and serum and to induce p53 degradation, inhibit p53 mediated transactivation, or bind E6BP. Evidently there are additional cellular targets for E6 which mediate this alteration in cellular differentiation.

Several species of alternatively spliced mRNAs are transcribed from the E6 gene region of human papillomavirus (HPV) 16. These have the coding capacity for either the full length E6 of 151 amino acids (aa) or four truncated variants, E6I-E6IV, of 43-64 aa. As the first step to identify the putative E6 variants and their functions, we generated cDNAs corresponding to the various E6 open reading frames (ORF) and examined their expression employing in vitro transcription/translation systems and the bacterial pET system. In wheat germ extract, in vitro translation resulted in the production of all five proteins, E6 and E6I-E6IV. These proteins were also expressed as stable fusion proteins from the pET16b and pET17 x b vectors in Escherichia coli. Mobilites of the E6 variant proteins on SDS-acrylamide gels were consistent with their predicted sizes. The authenticity of the synthesized proteins was confirmed by immunoprecipitation with specific antibodies directed against epitopes in the N-terminal portion of E6 as well as antibodies raised against the individual variant proteins produced in E. coli. In rabbit reticulocyte lysate, however, only the full length E6 and the E6IV variant were synthesized. This could be due to inefficient translation as well as lower stability of the short variants. E6I-III, in reticulocyte lysate (RTL). The ability of the E6 variants to associate with p53 and target its proteolytic degradation in vitro, was examined in coimmunoprecipitation assays, using in vitro synthesized proteins and monoclonal antibodies to p53. Results of these assays indicated that only the full length E6 efficiently binds to and promotes the degradation of p53. The E6 variants E6I-E6IV, although able to associate with p53 at a low efficiency, were unable to target its degradation.

The present study further investigated the mode of action of methyl jasmonate (MJ) in different cervical cancer cell lines. We show that in addition to the short term cytotoxicity, MJ effectively reduced the survival of cervical cancer cells (clonogenicity assays). MJ induced apoptosis in all cervical cancer cells. In some cell lines, MJ caused elevation of the mitochondrial superoxide anion, notably, in HeLa and CaSki. Changes in the expression of p53 and bax were variable, yet, downregulation of survivin was common to all cervical cancer cells. MJ significantly reduced the levels of the human papillomavirus (HPV) E6 and E7 proteins without alteration of the mRNA levels. Moreover, ectopic expression of E6, E7 or both in cervical cancer cells that lack HPV (C33A), did not alter significantly their response to MJ. Our studies point to MJ as an effective anticancer agent against a variety of cervical cancer cells acting through shared and different pathways to induce cell death regardless of the presence of HPV.

Expression of the E6 oncoprotein of human papillomavirus (HPV) 16 in primary human keratinocytes (PHKs) was previously shown to significantly reduce apoptosis. This could be due to increased cell adhesion. Adhesion ability was tested by seeding cells on tissue culture dishes coated with different concentrations of poly(HEME) and determination of the proportion of attached cells. Assays were carried out with PHKs, immortalized human keratinocytes (HaCaT) and human 293T cells. The E6 gene was transduced via retroviral infection or DNA transfection. Results of these assays showed that expression of E6 increased the proportion of cells that attached to poly(HEME). Several HPV16 E6 mutants were also tested in the above assay in 293T cells. These assays showed that the p53 targeting region of E6 is dispensable for this activity. Assays of inhibition of tyrosine kinases by bombesin showed that E6 probably utilizes other pathways to increase cell adhesion.

Genetic variations in the E6 oncogene have been associated with different risk for cancer progression. In the present study, the functional significance of human papillomavirus (HPV) polymorphism in the E6 oncogene was investigated. Ten HPV16 E6 variants containing amino acid substitutions in the N-terminal region of E6 were evaluated for different biological and biochemical activities in human keratinocytes, the target cells for HPV infection. Western blot analyses of primary foreskin human keratinocytes or immortalized human keratinocytes, stably transduced with the E6 variants, revealed reduced p53 and Bax levels in all E6 expressing cultures. The reduction induced by most E6 proteins was at similar levels and comparable to the reduction induced by the E6 prototype. The ability of the proteins to induce serum/calcium-differentiation resistant colonies in primary keratinocytes was more variable. Overall activities of the variants ranged between 0.24- and 2.18-fold of the E6 prototype activity. The I27R/L83V variant showed the lowest activity whereas the R8Q variant showed the highest activity. The L83V polymorphism previously associated with risk for cancer progression in some populations, showed significant activity, comparable to that of the E6 prototype, in reducing p53 and Bax levels. Furthermore, this variant showed enhancement in the ability to induce colonies resistant to serum/calcium-triggered differentiation, however, the difference from the prototype was not statistically significant. This, and augmentation of other described functions might result in differences in L83V pathogenicity.

Genetic studies have revealed natural amino acid variations within the human papillomavirus (HPV) type 16 E6 oncoprotein. To address the functional significance of E6 polymorphisms, 10 HPV16 E6 variants isolated from cervical lesions of Swedish women were evaluated for their activities in different in vitro and in vivo assays relevant to the carcinogenic potential of E6. Small differences between E6 prototype and variants, and among variants, were observed in transient expression assays that assessed p53 degradation, Bax degradation, and inhibition of p53 transactivation. More variable levels of activities were exhibited by the E6 proteins in assays that evaluated binding to the E6-binding protein (E6BP) or the human discs large protein (hDlg). The E6 prototype expressed moderate to high activity in the above assays. The L83V polymorphism, previously associated with risk for cancer progression in some populations, expressed similar levels of activity as that of the E6 prototype in most functional assays. On the other hand, L83V displayed more efficient degradation of Bax and binding to E6BP, but lower binding to hDlg. Results of this study indicate that naturally occurring amino acid variations in HPV16 E6 can alter activities of the protein important for its carcinogenic potential.

Transfection of human papillomavirus (HPV) 16 E6 oncogene into foreskin primary human keratinocytes (PHKs) causes the formation of colonies of viable cells resistant to serum–calcium differentiation. To define the stage of keratinocyte differentiation inhibited by E6, we examined the response of PHKs to serum and calcium with respect to parameters of both growth and differentiation. The effect of HPV16 E6 was evaluated by infection with recombinant retroviruses encoding the E6 protein. Results of these studies indicated that terminal differentiation of cultured foreskin keratinocytes, triggered by serum and calcium, is a progressive process (2–3 weeks) that ends with cell death with characteristics of apoptosis. Human keratinocyte terminal differentiation was accompanied by time-related changes in the expression of cellular proteins involved in the control pathways of apoptosis, including downregulation of Bcl-2 and p53 and upregulation of Bax, which coincided with the appearance of morphological signs of apoptosis. E6 expression did not override the differentiation-associated G1 arrest or prevent the induction of squamous differentiation-specific markers, transglutaminase 1 and involucrin. E6 expression led, however, to a significant reduction in cell stratification and cell death by apoptosis, which correlated with prolonged expression of Bcl-2 and reduced elevation of Bax levels that occurred concomitant with a complete loss of p53. The data argue that E6 inhibits terminal differentiation of foreskin PHKs through inhibition of their differentiation-induced apoptotic program.

Induction of apoptosis is a function of external stimuli and cellular gene expression. Many cells respond to DNA damage by the induction of apoptosis, which depends on a functional p53 protein and is signaled by elevation of p53 levels. We have investigated the response of immortalized human keratinocytes (HaCaT) bearing mutated alleles of p53 to genotoxic stress and the effect of human papillomavirus (HPV) 16 E6 and E7 on this response. UVC irradiation triggered HaCaT's cell death with several characteristics of apoptosis, including DNA laddering, chromatin condensation and fragmentation, and the appearance of cells with a low content of DNA (categorized as sub-G1 by cell sorter analysis). This response was accompanied by accumulation of cells in S phase of the cell cycle. HaCaT cells infected with retroviruses carrying HPV16 E6 or E7 showed a significant reduction in their apoptotic response, which was not observed in cells infected with the LXSN vector DNA-carrying virus. Reduced apoptosis in HaCaT cells expressing E6 or E7 also was observed after treatment with the alkylating agent mitomycin C. Western blot analysis of p53 and p21/WAF-1/CIP-1, a downstream effector of p53, did not reveal any changes in the levels of these proteins after UVC irradiation in either HaCaT cells or HaCaT cells expressing HPV16 E6 or E7.

In the present study, E6E7 and E6 proteins of human papillomaviruses (HPVs) associated with skin warts and cancer were compared for their transforming and carcinogenic abilities in primary human keratinocytes (PHKs). We show that E6E7 of cancer associated beta HPV types, notably 49 and 24, were able to extend the life span and enhance the clonogenic efficiency of PHKs when maintained in serum free/low calcium medium. Activities of the beta HPV E6E7 were lower than those of HPV16 E6E7. In contrast, E6 proteins from HPV types detected in skin warts or cancer, notably 10, 49 and 38, attenuated UVB induced protective responses in PHKs including cell death, proliferation arrest and accumulation of the proapoptotic proteins, p53, bax or bak. Together, this investigation revealed functional differences and commonalities between HPVs associated with skin warts and cancer, and allowed the identification of specific properties of beta HPVs supporting their involvement in skin carcinogenesis.