Selected publications

• Fox J L, Ismail F, Azad A, Ternette N, Leverrier S, Edelmann M J, Kessler B M, Leigh I M, Jackson S, and Storey A (2010) Tyrosine dephosphorylation is required for Bak activation in apoptosis. EMBO J, 29(22):3853-3868.

• Papadakis E S, Cichon M, Vyas J J, Patel N, Ghali L, Cerio R, Storey A, and O'Toole E A (2010) Axl Promotes Cutaneous Squamous Cell Carcinoma Survival through Negative Regulation of Pro-Apoptotic Bcl-2 Family Members. J Invest Dermatol.

• Tomlins C and Storey A (2010) Cutaneous HPV5 E6 causes increased expression of Osteoprotegerin and Interleukin 6 which contribute to evasion of UV induced apoptosis. Carcinogenesis.

• Akgul Baki, Zigrino Paola, Frith David, Hanrahan Sarah, and Storey Alan (2009) Proteomic analysis reveals the actin cytoskeleton as cellular target for the human papillomavirus type 8. Virology, 386(1):1-5.

• Martins Vera L, Vyas Jashmin J, Chen Mei, Purdie Karin, Mein Charles A, South Andrew P, Storey Alan, McGrath John A, and O'Toole Edel A (2009) Increased invasive behaviour in cutaneous squamous cell carcinoma with loss of basement-membrane type VII collagen. J Cell Sci, 122(Pt 11):1788-99.

Alan Storey

The inactivation of cell death pathways during tumour progression is a hallmark of cancer cells. This, coupled with the loss of function of apoptotic pathways, contributes towards drug resistance and this poses a major barrier to effective treatment of many cancers. We are interested in understanding the processes and identifying underlying mechanisms by which otherwise healthy cells become tumorigenic and fail to respond to endogenous or therapeutic signals to kill them is vital. Our recent work has identified a novel mechanism through which Bak, a key regulator of apoptosis at the mitochondria is controlled.
The Group has also made significant advances in our understanding of the molecular mechanisms by which human papillomavirus (HPV) can contribute towards skin cancer development. The focus of much our research effort in this area has been to better understand the mechanism by which HPV inhibits UV-induced apoptosis and how this can contribute towards the initial stages of cancer development. This had lead us to investigate basic biochemical mechanisms underlying apoptotic responses, and in particular how key regulators of mitochondrial apoptosis are activated, regulated and subsequently targeted for inactivation by HPV proteins. We use a range of molecular, proteomic and cell biology approaches to address our aims.

Our goals are to:

1. Investigate how apoptotic stimuli lead to the multi-step activation of Bak, a mitochondrial pro-apoptotic regulator;
2. Characterize the pathways involved in viral carcinogenesis, with particular reference to the inhibition of apoptotic pathways, and to determine the molecular basis of how they are subverted by HPV encoded proteins;
3. Exploit this information to investigate whether these pathways play a critical role in tumour development, and to examine the feasibility of targeting key regulators of Bak activation and HPV prteins in order to restore normal cellular function.

UV radiation is recognised as an important aetiological agent in the development of skin cancer. However, an exciting development in this area is the emerging and growing body of clinical and epidemiological evidence supporting a role for human papillomaviruses (HPVs) in the development of these cancers in both immunocompromised as well as immunocompetent. UV irradiation leads to the activation of cell cycle checkpoint controls as well as apoptotic pathways and their impairment may be an important step in tumourigenesis.  Investigating the mechanisms by which HPVs overcome cellular responses may therefore suggest ways of intervention, in addition to shedding light on the normal differentiation program and biological response of the epidermis to UV damage.

HPV Genome

In response to viral infection, human cells typically invoke a range of mechanisms that can either enhance cell survival or promote cell elimination, and viruses have evolved a host of mechanisms of inhibiting these pathways. Understanding how the virus co-ordinates the inhibition of these pathways provides us with a unique opportunity to investigate both how these pathways operate in normal cells, and investigate how to eliminate potentially tumourigenic cells by directly intervening to abolish specific viral activities. The group receives substantial direct funding from Cancer Research UK as well as other grant awarding bodies.

Key Findings and Current Research

• We have recently shown that the initial step in Bak activation depends upon dephosphorylation of the protein at tyrosine 108 (Y108). We used RNAi screening to identify the protein tyrosine phosphatases involved and showed how one, PTPN5, was regulated by MEK/ERK signaling that directly controlled Bak activation – see below

Protein tyrosine phosphatases respond to different stimuli to activate Bak

Much of our research has focused on the mechanism by which the HPVE6 protein preserves mitochondrial activity through the inactivation of Bak. We are currently investigating how Bak becomes activated in response to DNA damage and how E6 targets activated Bak for proteolysis.

• A mutational analysis of HPV5 E6 has identified key regions of the protein that are required for the inhibition of apoptosis and the ability to target the Bak protein for proteosomal degradation. This showed that the E6-AP ubiquitin ligase was dispensable for the ability of E6 to target Bak for proteolysis. Current investigations are aimed at identifying the ubiquitin ligase involved in E6-mediated proteolysis – see below.
• Since HPV-associated NMSC do not contain viral loads compatible with one copy or viral DNA per tumour cell, yet HPV-containing tumours have very low apoptotic rates implies that HPV exerts an anti-apoptotic ‘bystander effect’. We have recently identified factors secreted by HPV-containing cells that have an anti-apoptotic effect on surrounding non-HPV containing cells.

 Which forms of Bak does HPV E6 target for proteolysis?

Alan Storey is Editor in Chief of Molecular Cancer

Molecular Cancer is an open access, online journal that considers submissions on basic, translational and clinical research of cancer and related biomedical science.

• Online submission
• Fair and thorough peer review
• Publication upon acceptance
• Open access policy ensures research is highly visible and widely read