On Friday 23rd, Prof. Michele Carbone during his lecture at EMu 2017 school on mineral fibers presented for the first time the results of his outstanding research just published in Nature:
Although almost any tumour type has been reported in carriers of germline BAP1 mutations, there is a prevalence of mesothelioma, often caused by asbestos, and of skin cancers caused by ultraviolet radiation. These two environmental carcinogens induce DNA damage and cell death. The balance between DNA damage and cell death determines the outcome: the more DNA-damaged cells survive exposure, the higher the risk that one of them may grow into a malignancy. We discovered that BAP1 localizes in the endoplasmic reticulum (ER) where BAP1 deubiquitylates, stabilizes and modulates the activity of IP3R3. The IP3R3 on the ER regulates Ca2+ release from the ER to the mitochondria. The reduced BAP1 levels in BAP1 mutation carriers s result in reduced release of Ca2+ from the ER and in turn, to low levels of Ca2+ in the mitochondria which causes the reduced ability of BAP1+/- cells to execute apoptosis. Moreover, MM cells that lack BAP1 because of inherited or acquired mutations are resistant to chemotherapy-induced cell death, providing a rationale for the characteristic resistance of MM to chemotherapy.
See the Nature paper at: http://rdcu.be/ts3Z