Fbxo21, a member of the F-box family proteins, is a subunit of the E3 ubiquitin ligase complex called SCFs (SKP1-Cullin-F-box). It plays a crucial role in the ubiquitin-proteasome system, regulating protein levels by tagging substrates with polyubiquitin chains for degradation. It is involved in multiple pathways, such as cytokine-mediated signaling, PI3K pathway, and is important in various biological processes including cell proliferation, differentiation, and epithelial-to-mesenchymal transition [2,4]. Genetic models like knockout (KO) and conditional knockout (CKO) mouse models are valuable for studying its functions.

In acute myeloid leukemia (AML), silencing Fbxo21 in human-derived AML cell lines and primary patient samples leads to differentiation, inhibits tumor progression, and sensitizes cells to chemotherapy agents. It does so by ubiquitylating p85α, a regulatory subunit of the PI3K pathway, for degradation, thus decreasing PI3K signaling [1]. In gastric cancer, decreased Fbxo21 expression is associated with poor prognosis, and knockdown of Fbxo21 in cell lines affects the expression of EMT markers, and inhibits the EMT via down-regulation of Nr2f2 through ubiquitination and proteasomal degradation [2]. In osteoarthritis, FBXO21 is upregulated in the cartilage of patients and relevant animal models. In vivo and in vitro knockdown of FBXO21 suppresses OA-related cartilage degeneration, while overexpression promotes it. The mechanism involves FBXO21 inhibiting autophagy by interacting with and phosphorylating ERK [3]. In hematopoiesis-specific Fbxo21 conditional knockout mouse models, stressing the hematopoietic stem and progenitor cell (HSPC) populations with 5-fluorouracil injections results in decreased survival, despite minimal alterations during steady-state hematopoiesis. Silencing Fbxo21 in HSPCs leads to a loss in colony formation and an increase in cell differentiation in vitro [4].

In conclusion, Fbxo21 is an important regulator in multiple biological processes. Its functions have been revealed through various model-based research, especially KO/CKO mouse models. These studies have shown its significance in diseases like AML, gastric cancer, osteoarthritis, and in hematopoiesis, providing potential therapeutic targets for these disease areas.

References:

1. Dobish, Kasidy K, Wittorf, Karli J, Swenson, Samantha A, Hyde, R Katherine, Buckley, Shannon M. 2023. FBXO21 mediated degradation of p85α regulates proliferation and survival of acute myeloid leukemia. In Leukemia, 37, 2197-2208. doi:10.1038/s41375-023-02020-w. https://pubmed.ncbi.nlm.nih.gov/37689825/

2. Jiang, Yannan, Liu, Xinyu, Shen, Renbin, Gu, Xinhua, Qian, Weifeng. 2021. Fbxo21 regulates the epithelial-to-mesenchymal transition through ubiquitination of Nr2f2 in gastric cancer. In Journal of Cancer, 12, 1421-1430. doi:10.7150/jca.49674. https://pubmed.ncbi.nlm.nih.gov/33531987/

3. Lin, Zhiming, Miao, Jianing, Zhang, Tao, Feng, Xinyuan, Bai, Lunhao. 2021. JUNB-FBXO21-ERK axis promotes cartilage degeneration in osteoarthritis by inhibiting autophagy. In Aging cell, 20, e13306. doi:10.1111/acel.13306. https://pubmed.ncbi.nlm.nih.gov/33450132/

4. Wittorf, Karli J, Weber, Kasidy K, Swenson, Samantha A, Buckley, Shannon M. 2022. Ubiquitin E3 ligase FBXO21 regulates cytokine-mediated signaling pathways, but is dispensable for steady-state hematopoiesis. In Experimental hematology, 114, 33-42.e3. doi:10.1016/j.exphem.2022.08.002. https://pubmed.ncbi.nlm.nih.gov/35987460/