the DNA repair system lead to a predisposition for developing cancer. At least some of the PIAS proteins are implicated in DNA repair, and specifically in enhancing repair of double-stranded breaks. In cell culture, overexpression of PIAS3 demonstrated an increased resistance of HeLa cells to ionizing radiation. This indicates a significant role for PIAS3 in DNA repair. Additionally, overexpression of PIAS3 inhibited human lung cancer cell growth in vitro and rendered cancer cells up to twelve times more sensitive to chemotherapeutic drugs. While inhibition of PIAS by siRNAs led cancer cells to accelerate cell proliferation and demonstrate higher levels of resistance to chemotherapy drugs. In a study of human brain tissue samples from glioblastoma multiforme patients, PIAS3 expression was found to be reduced compared to the control brain tissue. Inhibition of PIAS3 resulted in increased glioblastoma propagation, while PIAS3 overexpression inhibited STAT-3 signaling and cell proliferation . Furthermore, patients with higher levels of BRCA1, PIAS1, and PIAS4 survived for a longer period of time in a retrospective study of advanced gastric cancer patients. Continuous activation of the JAK-STAT pathway can cause cancer in humans as well as less complex organisms such as Drosophila. Given the preliminary evidence and their effects on important signaling pathways involved in cancer, PIAS proteins may be interesting targets for the development of treatments for cancers or as sensitizers for chemotherapeutic drugs and radiation in BRCA-deficient cancers. In addition to its importance in various cancers, the JAK-STAT signaling pathway plays an important part in the human immune response and in particular with regards to adaptive immunity. Clinical proof of concept for the use of JAK inhibitors for treatment of autoimmune and inflammatory disease has been demonstrated by Pfizer's tofacitinib, a JAK inhibitor recently approved in the US for the treatment of rheumatoid arthritis. Additionally, tofacitinib is currently being studied for the treatment of ankylosing spondylitis, psoriatic arthritis, psoriasis, atopic dermatitis, and inflammatory bowel disease. Furthermore, STAT1 and STAT2 are essential factors in the cellular antiviral and adaptive immune defenses. PIAS proteins and other regulators are necessary for homeostasis and for fine tuning the immune response. PIAS proteins regulate STAT transcription through several mechanisms, and genetic studies in rodents have shown that PIAS1 plays an important physiological role in STAT1 regulation. Many of the 60 proteins that PIAS protein family is believed to interact with are immune regulatory factors. References External links PIAS protein entry at the