Genes versus Environment: cytoplasmic BAP1 determines the toxic response to environmental stressors in mesothelioma

Our plain-English summary of Genes versus Environment: cytoplasmic BAP1 determines the toxic response to environmental stressors in mesothelioma, by I. Amelio (Cell Death & Disease, 2017).

The study

• Author: I. Amelio
• Journal: Cell Death & Disease
• Published: 2017;8(6):e2907
• Type of article: News
• Cited by: 7 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

In plain English

This was a News and Commentary article, not original research. The author described two then-in-press studies by the Carbone, Pinton, Yang and Jia groups, both using fibroblasts from carriers and control members of two US families, 'W' (Wisconsin) and 'L' (Louisiana), in which germline BAP1 mutation had been linked to malignant mesothelioma after minimal asbestos exposure. As reported in the commentary, cell-fractionation experiments found BAP1 accumulated in the cytoplasm, specifically the endoplasmic reticulum (ER). BAP1+/- fibroblasts expressed 50% of the BAP1 protein level of control fibroblasts, the reduction mainly affected the ER fraction, and these cells released less calcium from the ER and were less sensitive to pro-apoptotic drugs. BAP1 was reported to bind and stabilise the ER calcium channel IP3R3. Crocidolite asbestos treatment of primary human mesothelial cells increased cytoplasmic calcium release and apoptosis, while depletion of BAP1 or IP3R3 promoted crocidolite asbestos/TNF-alpha-induced transformation of those cells. A second study reported a 'Warburg effect' in BAP1+/- fibroblasts and plasma metabolite profiles predicting genotype with 100% accuracy. The author concluded these studies clarified molecular aspects of cancer predisposition in BAP1+/- individuals.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: News and Commentary article (editorial commentary on two other, then-in-press studies); no new data generated by the author
• Who was studied: The commented studies used BAP1+/- and BAP1+/+ fibroblasts (and plasma) from carriers and control members of two unrelated US families, 'L' (Louisiana) and 'W' (Wisconsin), plus primary human mesothelial cells
• Exposure: Germline BAP1 heterozygous mutation as the genetic factor; crocidolite asbestos (alone and with TNF-alpha) applied to primary human mesothelial cells, with asbestos and UV named as environmental carcinogens in the background
• Main results:
  • In the commented work, cell-fractionation experiments showed BAP1 accumulated in the cytoplasm, specifically the endoplasmic reticulum
  • BAP1+/- fibroblasts contained 50% of the BAP1 protein of control fibroblasts
  • The reduced BAP1 level in BAP1+/- fibroblasts mainly affected the ER fraction of the protein
  • BAP1+/- cells were hyposensitive to a wide range of pro-apoptotic drugs and inducers, and BAP1+/- fibroblasts showed reduced calcium release from the ER
  • BAP1 was reported to physically interact with IP3R3 and to control its ubiquitination and stability
  • In primary mesothelial cells, depleting BAP1 or IP3R3 promoted crocidolite asbestos/TNF-alpha-induced transformation; re-expressing IP3R3 partially reversed this
  • The second commented study reported a 'Warburg effect' in BAP1+/- fibroblasts
  • Plasma metabolite profiles of carrier individuals predicted genotype with 100% accuracy
• The authors' conclusion: The author concluded that the two studies clarified molecular aspects of cancer predisposition in BAP1+/- individuals and raised new questions about gene/environment interactions
• Limitations the authors state:
  • The author stated that the relative contribution of cytoplasmic versus nuclear BAP1 remains open, since both contributed to the phenotype
  • The author stated that the link between the metabolic changes and calcium flux/ER-mitochondria function is unresolved

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: BAP1, Mesothelioma.

Related studies

• BAP1 forms a trimer with HMGB1 and HDAC1 that modulates gene × environment interaction with asbestos — F. Novelli, A. Bononi, et al. (2021)
• BAP1 Status Determines the Sensitivity of Malignant Mesothelioma Cells to Gemcitabine Treatment — A. Guazzelli, P. Meysami, et al. (2019)
• Comparison of Germline versus Somatic BAP1 Mutations for Risk of Metastasis in Uveal Melanoma — K.G. Ewens, E. Lalonde, et al. (2018)
• Utility of BRCA1-associated protein 1 immunoperoxidase stain to differentiate benign versus malignant mesothelial proliferations in cytologic specimens — Z. McCroskey, G. Staerkel, et al. (2017)
• Cytological diagnosis of mesothelioma in situ versus invasive mesothelioma — A. Churg, F. Galateau-Salle, et al. (2022)
• Frequent inactivation of the BAP1 gene in epithelioid-type malignant mesothelioma — Y. Yoshikawa, A. Sato, et al. (2012)

Browse more research in Cell Death & Disease, or return to medical research.