Bag4, also known as Bcl-2-associated athanogene 4 and SODD (silencer of death domains), is a molecular chaperone regulator. Its BAG domain binds to Hsp70/Hsc70 family proteins and modulates their activity. Bag4 is involved in multiple biological processes and associated pathways, such as being potentially linked to the TNFalpha-TNFR1 signaling pathway and having a role in cell survival regulation [2,6]. It is also of significance in plant stomatal movement regulation by interacting with the KAT1 potassium channel [5].

In sheep, copy number variation (CNV) of the Bag4 gene is associated with growth traits. The CNV shows different distributions among different sheep breeds, and is significantly related to body height, body slanting length, and hip cross height in specific Chinese sheep breeds, suggesting its potential as a molecular breeding marker [1]. In gastric cancer, Bag4 promotes cell proliferation, migration, invasion, and metastasis. It activates the PI3K/AKT/NF-κB/ZEB1 axis to induce epithelial-mesenchymal transition, and its overexpression is correlated with poor patient outcomes [3,4]. Also, in some cancer types, the 8p11.23 locus where Bag4 is located shows recurrent amplifications, which may contribute to neoplastic processes [7].

In conclusion, Bag4 plays essential roles in various biological processes and diseases. In sheep, its CNV impacts growth traits, while in gastric cancer, it acts as an oncogene promoting cancer cell progression. The amplification of the locus containing Bag4 in some cancers further highlights its significance in neoplastic development. Studies on Bag4 contribute to understanding the molecular mechanisms underlying growth and cancer, potentially providing new targets for molecular breeding in sheep and cancer therapy.

References:

1. Yang, Zhaoxin, Cao, Xiukai, Ma, Yilei, Hu, Linyong, Chen, Hong. 2020. Novel copy number variation of the BAG4 gene is associated with growth traits in three Chinese sheep populations. In Animal biotechnology, 32, 461-469. doi:10.1080/10495398.2020.1719124. https://pubmed.ncbi.nlm.nih.gov/32022644/

2. Briknarová, Klara, Takayama, Shinichi, Homma, Sachiko, Satterthwait, Arnold C, Ely, Kathryn R. 2002. BAG4/SODD protein contains a short BAG domain. In The Journal of biological chemistry, 277, 31172-8. doi:. https://pubmed.ncbi.nlm.nih.gov/12058034/

3. Yi, Lizhi, Lv, Zhenbing, Wang, Jianmei, Zhong, Xianfei. 2017. Bcl‑2 associated athanogene 4 promotes proliferation, migration and invasion of gastric cancer cells. In Molecular medicine reports, 16, 3753-3760. doi:10.3892/mmr.2017.7073. https://pubmed.ncbi.nlm.nih.gov/29067445/

4. Jiang, Lei, Chen, Yan, Min, Guangtao, Wang, Xiangwen, Yao, Nan. 2021. Bcl2-associated athanogene 4 promotes the invasion and metastasis of gastric cancer cells by activating the PI3K/AKT/NF-κB/ZEB1 axis. In Cancer letters, 520, 409-421. doi:10.1016/j.canlet.2021.08.020. https://pubmed.ncbi.nlm.nih.gov/34419501/

5. Locascio, Antonella, Marqués, Maria Carmen, García-Martínez, Guillermo, Mulet, José Miguel, Yenush, Lynne. 2019. BCL2-ASSOCIATED ATHANOGENE4 Regulates the KAT1 Potassium Channel and Controls Stomatal Movement. In Plant physiology, 181, 1277-1294. doi:10.1104/pp.19.00224. https://pubmed.ncbi.nlm.nih.gov/31451552/

6. Eichholtz-Wirth, H, Sagan, D. . Altered signaling of TNFalpha-TNFR1 and SODD/BAG4 is responsible for radioresistance in human HT-R15 cells. In Anticancer research, 22, 235-40. doi:. https://pubmed.ncbi.nlm.nih.gov/12017295/

7. Voutsadakis, Ioannis A. 2020. Amplification of 8p11.23 in cancers and the role of amplicon genes. In Life sciences, 264, 118729. doi:10.1016/j.lfs.2020.118729. https://pubmed.ncbi.nlm.nih.gov/33166592/