Cdkn2aip, also known as CDKN2A interacting protein or CARF, is a member of the RNA-binding protein family. It has been shown to be crucial for stem cell pluripotency and somatic differentiation. Cdkn2aip is involved in multiple pathways, such as activating the Wnt-signaling pathway, which is essential for spermatogonial self-renewal and proliferation [1].

Cdkn2aip-/-male mice exhibit multiple sperm head defects, age-dependent germ cell loss, synapsis failure in spermatocytes, increased apoptosis due to impaired DNA double-strand break repair and crossover formation [1]. In testicular seminoma, up-regulation of Cdkn2aip inhibits tumor growth and increases cell senescence and apoptosis by interacting with CARM1 and eIF4β [2]. In nasopharyngeal carcinoma, higher expression of Cdkn2aip is associated with radioresistance, and its knockout opposes the proliferation of NPC cells [3]. In osteosarcoma, circFOXP1 promotes angiogenesis by regulating the miR-127-5p/CDKN2AIP signaling pathway [4]. NR4A3 can directly regulate the expression of CDKN2AIP at the transcriptional level to suppress the development of hepatocellular carcinoma [5]. Also, fatty acid excess downregulates hepatic Cdkn2aip, and its overexpression alleviates hepatic steatosis, ER stress, oxidative stress, and insulin resistance [6].

In conclusion, Cdkn2aip plays essential roles in germ cell development, spermatogenesis, and tumor-related processes such as cell senescence, apoptosis, and radioresistance. The study of Cdkn2aip knockout mouse models has provided valuable insights into its functions in these biological processes and disease conditions, contributing to a better understanding of the underlying mechanisms and potentially offering new therapeutic targets for related diseases.

References:

1. Cao, Yuming, Sun, Qi, Chen, Zhenlie, Ma, Ling, Zhang, Yuanzhen. 2022. CDKN2AIP is critical for spermiogenesis and germ cell development. In Cell & bioscience, 12, 136. doi:10.1186/s13578-022-00861-z. https://pubmed.ncbi.nlm.nih.gov/35989335/

2. Cao, Yuming, Chen, Zhenlie, Qin, Zihan, Liu, Tongzu, Zhang, Yuanzhen. . CDKN2AIP-induced cell senescence and apoptosis of testicular seminoma are associated with CARM1 and eIF4β. In Acta biochimica et biophysica Sinica, 54, 604-614. doi:10.3724/abbs.2022040. https://pubmed.ncbi.nlm.nih.gov/35593475/

3. Zhou, Ziyan, Chen, Gang, Shen, Mingjun, Chen, Weimin, Kang, Min. 2023. Genome-scale CRISPR-Cas9 knockout screening in nasopharyngeal carcinoma for radiosensitive and radioresistant genes. In Translational oncology, 30, 101625. doi:10.1016/j.tranon.2023.101625. https://pubmed.ncbi.nlm.nih.gov/36739730/

4. Zhang, Haiping, Yu, Ziliang, Wu, Bingbing, Sun, Farui. . Circular RNA circFOXP1 promotes angiogenesis by regulating microRNA -127-5p/CDKN2AIP signaling pathway in osteosarcoma. In Bioengineered, 12, 9991-9999. doi:10.1080/21655979.2021.1989258. https://pubmed.ncbi.nlm.nih.gov/34637672/

5. Zhao, Xinge, Min, Xuejie, Wang, Zhenyu, Chen, Taoyang, Li, Jinjun. 2024. NR4A3 inhibits the tumor progression of hepatocellular carcinoma by inducing cell cycle G0/G1 phase arrest and upregulation of CDKN2AIP expression. In International journal of biological sciences, 20, 5850-5867. doi:10.7150/ijbs.95174. https://pubmed.ncbi.nlm.nih.gov/39664575/

6. Hasan, Kamrul M, Parveen, Meher, Pena, Alondra, Sinha-Hikim, Amiya P, Friedman, Theodore C. 2023. Fatty Acid Excess Dysregulates CARF to Initiate the Development of Hepatic Steatosis. In Cells, 12, . doi:10.3390/cells12071069. https://pubmed.ncbi.nlm.nih.gov/37048142/