Bbc3, also known as BCL2 binding component 3 or PUMA, is a key pro-apoptotic gene. It plays significant roles in the regulation of cell apoptosis and is involved in multiple cellular pathways, such as autophagy-apoptosis interplay. Its importance extends to various biological processes and disease conditions [1-10].

In a mouse miscarriage model, knockdown of murine Bbc3 could efficiently suppress placental apoptosis and alleviate miscarriage, indicating its role in trophoblast cell apoptosis and miscarriage [1]. In the mouse model of silicosis, Bbc3 knockout mice clearly exhibited decreased levels of autophagy and fibrosis progression, suggesting that Bbc3 in macrophages promotes pulmonary fibrosis development through inducing autophagy during silicosis [2]. In mouse primary cortical neuronal cultures exposed to the organophosphate pesticide chlorpyrifos, Bbc3 loss attenuated CPF-driven neurotoxicity, induction of other intrinsic apoptosis regulatory genes, and cleavage of apoptosis executors [3]. In Bbc3 -/- neuronal cultures, elevated autophagy-related protein expression was associated with a reduction in CPF-induced high molecular weight protein aggregates [3]. In a mouse model for methamphetamine-mediated neurotoxicity, anti-Mir143-dependent BBC3 upregulation reversed the methamphetamine-induced decrease in microglial survival via the regulation of apoptosis and autophagy [4]. In an islet injury model mediated by cold preservation and rewarming, Bbc3-KO islets from cold-preserved pancreata showed reduced HMGB1 expression and decreased levels of 4-hydroxynonenal protein adducts, indicating reduced oxidative stress [5].

In conclusion, Bbc3 is a crucial gene in regulating apoptosis, and its loss-of-function models, especially KO mouse models, have revealed its role in various disease conditions such as miscarriage, silicosis, neurodegenerative diseases related to environmental toxicants, methamphetamine-mediated neurotoxicity, and islet injury during cold preservation and rewarming. Understanding Bbc3's function through these models provides insights into disease mechanisms and potential therapeutic targets.

References:

1. Zhao, Jingsong, Xu, Zhongyan, Xie, Jiayu, Guo, Jiarong, Zhang, Huidong. 2024. The novel lnc-HZ12 suppresses autophagy degradation of BBC3 by preventing its interactions with HSPA8 to induce trophoblast cell apoptosis. In Autophagy, 20, 2255-2274. doi:10.1080/15548627.2024.2362122. https://pubmed.ncbi.nlm.nih.gov/38836496/

2. Liu, Haijun, Cheng, Yusi, Yang, Jian, Chao, Jie, Liao, Hong. 2017. BBC3 in macrophages promoted pulmonary fibrosis development through inducing autophagy during silicosis. In Cell death & disease, 8, e2657. doi:10.1038/cddis.2017.78. https://pubmed.ncbi.nlm.nih.gov/28277537/

3. Anderson, Faith L, von Herrmann, Katharine M, Young, Alison L, Havrda, Matthew C. . Bbc3 Loss Enhances Survival and Protein Clearance in Neurons Exposed to the Organophosphate Pesticide Chlorpyrifos. In Toxicological sciences : an official journal of the Society of Toxicology, 183, 378-392. doi:10.1093/toxsci/kfab090. https://pubmed.ncbi.nlm.nih.gov/34289071/

4. Zhang, Yuan, Shen, Kai, Bai, Ying, Hu, Gang, Yao, Honghong. 2016. Mir143-BBC3 cascade reduces microglial survival via interplay between apoptosis and autophagy: Implications for methamphetamine-mediated neurotoxicity. In Autophagy, 12, 1538-59. doi:10.1080/15548627.2016.1191723. https://pubmed.ncbi.nlm.nih.gov/27464000/

5. Omori, Keiko, Kobayashi, Eiji, Komatsu, Hirotake, Takahashi, Masafumi, Mullen, Yoko. 2016. Involvement of a proapoptotic gene (BBC3) in islet injury mediated by cold preservation and rewarming. In American journal of physiology. Endocrinology and metabolism, 310, E1016-26. doi:10.1152/ajpendo.00441.2015. https://pubmed.ncbi.nlm.nih.gov/27117005/