Rgs12, the largest protein in the RGS protein family, is a crucial regulator in multiple biological processes. It is involved in G-protein signaling pathways and plays a significant role in inflammation, bone remodeling, and tumorigenesis. Genetic models, especially KO/CKO mouse models, have been instrumental in understanding its functions [1-10].

In periodontitis, ablation of Rgs12 in Mx1+ hematopoietic cells blocked bone loss, inhibited osteoclast formation and activity, as well as production of inflammatory cytokines [1]. In osteosarcoma, depletion of Rgs12 promoted tumor progression and lung metastasis, and it was identified as a tumor suppressor inhibiting the YAP-TEAD1-Ezrin signaling pathway [2]. In inflammatory arthritis, deletion of Rgs12 in myeloid lineage or globally inhibited the disease development, and Rgs12 was found to be a critical NF-κB activator [3]. In oral cancer, Rgs12 knockout mice showed more aggressive tumors, and Rgs12 repressed oral cancer via phosphorylation and SUMOylation of PTEN [4]. In osteoarthritis, Rgs12 deficiency in macrophages prevented ubiquitination, inflammation, and cartilage damage [5]. In oral squamous cell carcinoma, Rgs12 knockout in macrophages decreased M1 TAMs and increased cancer cell proliferation and invasion [6]. In sensory hair cells, Rgs12 was required to polarize the GPSM2-GNAI complex for stereocilia organization [7]. In skeletal development, deletion of Rgs12 in type II collagen-positive cells led to mitochondrial function defects [8]. In inflammatory arthritis, Rgs12 promoted angiogenesis through governing ciliogenesis in endothelial cells [9]. In African American prostate cancer, Rgs12 was identified as a tumor-suppressor gene repressing AKT and MNX1 expression [10].

In conclusion, Rgs12 is essential in regulating inflammation, bone remodeling, and tumorigenesis. KO/CKO mouse models have revealed its roles in diseases such as periodontitis, osteosarcoma, inflammatory arthritis, oral cancer, osteoarthritis, and prostate cancer, providing valuable insights into disease mechanisms and potential therapeutic targets.

References:

1. Yuan, G, Fu, C, Yang, S T, Hajishengallis, G, Yang, S. 2021. RGS12 Drives Macrophage Activation and Osteoclastogenesis in Periodontitis. In Journal of dental research, 101, 448-457. doi:10.1177/00220345211045303. https://pubmed.ncbi.nlm.nih.gov/34796776/

2. Li, Yang, Liu, Min, Yang, Shuting, Karin Eisinger-Mathason, T S, Yang, Shuying. 2021. RGS12 is a novel tumor suppressor in osteosarcoma that inhibits YAP-TEAD1-Ezrin signaling. In Oncogene, 40, 2553-2566. doi:10.1038/s41388-020-01599-z. https://pubmed.ncbi.nlm.nih.gov/33686240/

3. Yuan, Gongsheng, Yang, Shuting, Ng, Andrew, Xing, Lianping, Yang, Shuying. 2020. RGS12 Is a Novel Critical NF-κB Activator in Inflammatory Arthritis. In iScience, 23, 101172. doi:10.1016/j.isci.2020.101172. https://pubmed.ncbi.nlm.nih.gov/32512384/

4. Fu, C, Yuan, G, Yang, S T, Zhang, D, Yang, S. 2020. RGS12 Represses Oral Cancer via the Phosphorylation and SUMOylation of PTEN. In Journal of dental research, 100, 522-531. doi:10.1177/0022034520972095. https://pubmed.ncbi.nlm.nih.gov/33198557/

5. Yuan, Gongsheng, Yang, Shuting, Yang, Shuying. 2021. Macrophage RGS12 contributes to osteoarthritis pathogenesis through enhancing the ubiquitination. In Genes & diseases, 9, 1357-1367. doi:10.1016/j.gendis.2021.08.005. https://pubmed.ncbi.nlm.nih.gov/35873013/

6. Yuan, Gongsheng, Yang, Shuting, Yang, Shuying. 2023. RGS12 represses oral squamous cell carcinoma by driving M1 polarization of tumor-associated macrophages via controlling ciliary MYCBP2/KIF2A signaling. In International journal of oral science, 15, 11. doi:10.1038/s41368-023-00216-5. https://pubmed.ncbi.nlm.nih.gov/36797232/

7. Akturk, Anil, Day, Matthew, Tarchini, Basile. 2022. RGS12 polarizes the GPSM2-GNAI complex to organize and elongate stereocilia in sensory hair cells. In Science advances, 8, eabq2826. doi:10.1126/sciadv.abq2826. https://pubmed.ncbi.nlm.nih.gov/36260679/

8. Yuan, Gongsheng, Yang, Shuting, Liu, Min, Yang, Shuying. 2020. RGS12 is required for the maintenance of mitochondrial function during skeletal development. In Cell discovery, 6, 59. doi:10.1038/s41421-020-00190-w. https://pubmed.ncbi.nlm.nih.gov/32922858/

9. Yuan, Gongsheng, Yang, Shu-Ting, Yang, Shuying. 2022. Endothelial RGS12 governs angiogenesis in inflammatory arthritis by controlling cilia formation and elongation via MYCBP2 signaling. In Cell insight, 1, 100055. doi:10.1016/j.cellin.2022.100055. https://pubmed.ncbi.nlm.nih.gov/37193553/

10. Wang, Yongquan, Wang, Jianghua, Zhang, Li, Creighton, Chad J, Ittmann, Michael. 2017. RGS12 Is a Novel Tumor-Suppressor Gene in African American Prostate Cancer That Represses AKT and MNX1 Expression. In Cancer research, 77, 4247-4257. doi:10.1158/0008-5472.CAN-17-0669. https://pubmed.ncbi.nlm.nih.gov/28611045/