Mkrn2, an evolutionarily conserved gene, encodes an E3 ubiquitin-protein. It is involved in multiple biological processes, with its protein product having the ability to regulate protein degradation through ubiquitination. It plays a role in pathways such as those related to NF-κB-mediated inflammatory responses, mRNA nuclear export, and is potentially associated with many diseases [3,8]. Genetic models, especially knockout mouse models, have been crucial in studying Mkrn2's functions.

In mice, deletion of Mkrn2 leads to male infertility. This is due to decreased expression of STAT1, SIX4, and TNC, and abnormal apoptosis in the testis through the p53/PERP-mediated pathway [2,5]. In zebrafish, knockdown or knockout of MKRN2 affects retinal development by interacting with GLE1 to regulate mRNA nuclear export [3]. In cancer research, MKRN2 is down-regulated in gastric cancer, and its overexpression inhibits cell proliferation by promoting ubiquitination-mediated degradation of PKM2 [1]. In colorectal carcinoma, the LINC00294/miR-620/MKRN2 axis negatively regulates malignant progression [4]. In ovarian cancer, overexpression of MKRN2 reduces tumor-associated behavior and induces apoptosis [6]. In non-small-cell lung cancer, MKRN2 inhibits cell migration and invasion by negatively regulating the PI3K/Akt pathway [7]. However, in melanoma, MKRN2 promotes cell proliferation by ubiquitinating P53 [9].

In conclusion, Mkrn2 is essential for male fertility, retinal development, and plays diverse roles in various cancers. The gene knockout models in mice and zebrafish have been instrumental in uncovering these functions, highlighting its significance in understanding male infertility and cancer development mechanisms.

References:

1. Liu, Zheng, Xiang, Shuyao, Guo, Xingchen, Kou, Jiaxin, Zhang, Jun. 2022. MKRN2 inhibits the proliferation of gastric cancer by downregulating PKM2. In Aging, 14, 2004-2013. doi:10.18632/aging.203643. https://pubmed.ncbi.nlm.nih.gov/35196650/

2. Wang, Lin, Yong, Yan-Ling, Wang, Kun-Kun, Qiu, Jian-Ge, Jiang, Bing-Hua. 2023. MKRN2 knockout causes male infertility through decreasing STAT1, SIX4, and TNC expression. In Frontiers in endocrinology, 14, 1138096. doi:10.3389/fendo.2023.1138096. https://pubmed.ncbi.nlm.nih.gov/36967804/

3. Wolf, Eric J, Miles, Amanda, Lee, Eliza S, Tropepe, Vincent, Emili, Andrew. . MKRN2 Physically Interacts with GLE1 to Regulate mRNA Export and Zebrafish Retinal Development. In Cell reports, 31, 107693. doi:10.1016/j.celrep.2020.107693. https://pubmed.ncbi.nlm.nih.gov/32460013/

4. Qi, Puliang, Yexie, Zhihua, Xue, Chen, Zhao, Zhanxue, Zhang, Xikun. . LINC00294/miR-620/MKRN2 axis provides biomarkers and negatively regulates malignant progression in colorectal carcinoma. In Human & experimental toxicology, 42, 9603271231167577. doi:10.1177/09603271231167577. https://pubmed.ncbi.nlm.nih.gov/37218161/

5. Qian, Ying-Chen, Xie, Yun-Xia, Wang, Chao-Shan, Wang, Lin, Jiang, Bing-Hua. . Mkrn2 deficiency induces teratozoospermia and male infertility through p53/PERP-mediated apoptosis in testis. In Asian journal of andrology, 22, 414-421. doi:10.4103/aja.aja_76_19. https://pubmed.ncbi.nlm.nih.gov/31489847/

6. Jiang, F Z, Xia, Q J, Wu, L, Zhang, Y M. . [Overexpression of MKRN2 Inhibits the Growth of Ovarian Cancer Cells]. In Molekuliarnaia biologiia, 57, 687-688. doi:. https://pubmed.ncbi.nlm.nih.gov/37528788/

7. Jiang, Jun, Xu, Yitong, Ren, Hongjiu, Jiang, Lihong, Qiu, Xueshan. 2018. MKRN2 inhibits migration and invasion of non-small-cell lung cancer by negatively regulating the PI3K/Akt pathway. In Journal of experimental & clinical cancer research : CR, 37, 189. doi:10.1186/s13046-018-0855-7. https://pubmed.ncbi.nlm.nih.gov/30103781/

8. Shin, Chanyoung, Ito, Yuma, Ichikawa, Shota, Sakata-Sogawa, Kumiko, Tanaka, Takashi. 2017. MKRN2 is a novel ubiquitin E3 ligase for the p65 subunit of NF-κB and negatively regulates inflammatory responses. In Scientific reports, 7, 46097. doi:10.1038/srep46097. https://pubmed.ncbi.nlm.nih.gov/28378844/

9. Zhang, Yiling, Cui, Ningning, Zheng, Gang. 2020. Ubiquitination of P53 by E3 ligase MKRN2 promotes melanoma cell proliferation. In Oncology letters, 19, 1975-1984. doi:10.3892/ol.2020.11261. https://pubmed.ncbi.nlm.nih.gov/32194692/