Cells experience various proteotoxic stress, which causes severe damages unless managed by cellular stress responses. These include the heat shock response, hypoxic stress response, osmotic stress response, unfolded protein response, and oxidative stress response. A key regulator of cellular stress responses is the transcription factor family called heat shock factors (HSFs). One of the main interests in our laboratory is to understand the functions of HSF1 and HSF2 in response to distinct proteotoxic stresses, including oxidative stress, proteasome inhibition and repeated heat stress. We believe that depending on a cellular state, HSF1 and HSF2 can have various functions beyond the conventional heat shock response, which involves the inducible expression of heat shock proteins (Hsps). This idea is supported by many genome-wide screens performed by us and others, revealing that both HSF1 and HSF2 localize to promoters and other regulatory regions of several genes unrelated to chaperone machinery and protein folding. In order to uncover the functional impact of HSFs in different biological contexts, we utilize high-throughput methods such as ChIP-seq, PRO-seq, and RNA-seq .
For more information on our ongoing projects and methods we use, please visit our website: http://sistonenlab.com!
Cellular Stress Responses. To maintain their function in the events of stress, cells activate specific transcriptional programs. Exposure to protein damaging stresses, such as elevated temperatures, ethanol, heavy metals, and microbial infections, activate the Heat Shock Response. When the cell encounters insufficient O2 availability, the Hypoxic Stress Response is activated. The influx of water from (hyperosmotic stress) or into (hypoosmotic stress) the cell, results in mounting the Osmotic Stress Response. Protein misfolding in specific organelles activates the Unfolded Protein Response (UPR), either in mitochondria (UPRmt) or endoplasmatic reticulum (UPRER). Uncontrolled increase in reactive oxygen species (ROS) turns on the Oxidative Stress Response.
Human papillomavirus (HPV) infection is a major global health issue. HPV infection is a well-established cause of cervical cancer and a relevant factor in other anogenital cancers as well as head and neck cancers. One common denominator of the HPV genotypes is the E6 and E7 proteins, which are mainly responsible for malignant and non-malignant phenotypes. Hence, they represent valuable targets for therapeutic intervention in HPV-driven cancers as no specific therapies are available till date. Our research group has identified a new therapeutic strategy to eliminate the E6 and E7 oncogenes. Based on the discovered strategy, we have developed several anti-HPV compounds, with anisomelic acid (AA) as the mother compound and a whole line of synthetic derivatives. We found that these compounds target HPV by depleting E6 and E7 oncogenes with exceptionally high specificity to the infected cells. To the best of our knowledge, this is the first report on a successful therapeutic strategy to specifically target HPV. We are currently studying detailed mechanism of the compounds degrading the oncoproteins, E6 & E7. Understanding the mechanisms by which E6 and E7 are degraded will provide insights that will advance our knowledge for targeting HPV cancers. We are also assessing the efficacy of AA and its derivatives in HPV lesions found in transgenic HPV mice model and using this mice model can help us in assessing the efficacy of our targeting therapy in preventing or formation of the HPV tumors. On the other hand, our another ongoing adventurous project is establishing a novel dual-targeting therapeutic strategy, that targets both the unique E6 and E7 -dependent features and the general stress protection machinery to eliminate HPV-driven cancers.
More about the research can be found at https://hpvhorizon.com/
Driven by the market need in the treatment of HPV-associated warts, our research team had developed a natural ointment/cream targeting HPV-driven warts. This innovative product is based on anti-HPV diterpenoid compound AA and other related compounds isolated from a traditional medicinal plant. This led to a University based spin-off, Anison Therapeutics which was established in 2021 to further take the product through regulatory pathway to the market.
The details about the startup can be found in the following link: https://anisontherapeutics.com/