Wdr76, a member of the WD40 repeat domain-containing proteins, is potentially involved in DNA damage repair, apoptosis, cell cycle progression, and gene expression regulation. The WD40 repeat domain is a prevalent protein-interaction domain in the human proteome, and proteins with this domain are likely to play important roles in various biological processes [1].

In in vivo studies, Wdr76-/-mice showed resistance to high-fat diet (HFD)-induced obesity, insulin resistance, and hyperlipidemia with increased HRas levels, while liver-specific Wdr76 transgenic mice (Wdr76Li-TG) had the opposite phenotypes, suggesting Wdr76 controls HFD-induced obesity and hepatic steatosis via HRas destabilization [2]. In colorectal cancer, Wdr76-/-mice displayed crypt elongation, hyper-proliferation, and more tumors with increased cancer stem cell activation when crossed with ApcMin / + mice, indicating that Wdr76 can degrade RAS and suppress cancer stem cell activation [3]. Also, Wdr76-/-mice were more susceptible to diethylnitrosamine-induced liver carcinogenesis, and liver-specific WDR76 induction reduced tumorigenesis in HRasG12V mouse livers, showing its role as a tumor suppressor via RAS degradation [4].

In conclusion, model-based research, especially using Wdr76 knockout mouse models, has revealed that Wdr76 plays crucial roles in regulating metabolism-related diseases like obesity and hepatic steatosis, as well as in tumorigenesis. Its function in destabilizing RAS seems to be a key mechanism in these processes, providing potential therapeutic targets for related diseases.

References:

1. Yang, Jie, Wang, Fei, Chen, Baoan. 2021. The role of WDR76 protein in human diseases. In Bosnian journal of basic medical sciences, 21, 528-534. doi:10.17305/bjbms.2020.5506. https://pubmed.ncbi.nlm.nih.gov/33714259/

2. Park, Jong-Chan, Jeong, Woo-Jeong, Seo, Seol Hwa, Choi, Kang-Yell. 2019. WDR76 mediates obesity and hepatic steatosis via HRas destabilization. In Scientific reports, 9, 19676. doi:10.1038/s41598-019-56211-6. https://pubmed.ncbi.nlm.nih.gov/31873167/

3. Ro, Eun Ji, Cho, Yong-Hee, Jeong, Woo-Jeong, Min, Do Sik, Choi, Kang-Yell. 2019. WDR76 degrades RAS and suppresses cancer stem cell activation in colorectal cancer. In Cell communication and signaling : CCS, 17, 88. doi:10.1186/s12964-019-0403-x. https://pubmed.ncbi.nlm.nih.gov/31362761/

4. Jeong, Woo-Jeong, Park, Jong-Chan, Kim, Woo-Shin, Min, Do Sik, Choi, Kang-Yell. 2019. WDR76 is a RAS binding protein that functions as a tumor suppressor via RAS degradation. In Nature communications, 10, 295. doi:10.1038/s41467-018-08230-6. https://pubmed.ncbi.nlm.nih.gov/30655611/