Mxd4, also known as MAD4, is a transcription factor and a member of the Myc-Max-Mad network [1,2,3]. It functions as a MYC antagonist, regulating important biological processes such as cell proliferation, differentiation, and cell fate decisions [1,2,3]. It is involved in multiple pathways, which are crucial for maintaining normal cellular functions and preventing diseases [1,2,3]. Genetic models, such as gene knockout mouse models, can be valuable tools for studying Mxd4's functions.

In human keratinocyte (KC) precursors, Mxd4 is expressed at a higher level in quiescent KC stem/progenitor cells. Decreased Mxd4 expression increases MYC expression, enhancing KC precursor proliferation, clonogenic potential, and functionality in 3D epidermis organoid generation, highlighting its role in regulating KC precursor fate [1]. In myeloid leukemia, depletion of UHRF1 or SAP30 derepresses Mxd4, suppressing leukemogenesis, while further knockdown of Mxd4 can rescue leukemogenesis by activating the MYC pathway, indicating its significance in AML [2]. In CD8+ T cells, CDK4/6 inhibition upregulates Mxd4, promoting CD8 T-cell memory formation, and silencing Mxd4 demonstrates its importance in this process [3].

In summary, Mxd4 is a key regulator in multiple biological processes. Its role as a MYC antagonist is evident in regulating cell proliferation and differentiation in various cell types. Through model-based research, Mxd4 has been shown to be involved in diseases like leukemia and potentially in cancer immunotherapy, as it impacts CD8+ T-cell memory formation. These findings enhance our understanding of normal cellular function and disease mechanisms related to Mxd4.

References:

1. Coutier, Julien, Auvré, Frédéric, Lemaître, Gilles, Martin, Michèle T, Fortunel, Nicolas O. 2022. MXD4/MAD4 Regulates Human Keratinocyte Precursor Fate. In The Journal of investigative dermatology, 143, 105-114.e12. doi:10.1016/j.jid.2022.07.020. https://pubmed.ncbi.nlm.nih.gov/36007550/

2. Hu, Cheng-Long, Chen, Bing-Yi, Li, Zijuan, Zheng, Mingyue, Wang, Lan. 2022. Targeting UHRF1-SAP30-MXD4 axis for leukemia initiating cell eradication in myeloid leukemia. In Cell research, 32, 1105-1123. doi:10.1038/s41422-022-00735-6. https://pubmed.ncbi.nlm.nih.gov/36302855/

3. Heckler, Max, Ali, Lestat R, Clancy-Thompson, Eleanor, Tolaney, Sara M, Dougan, Stephanie K. 2021. Inhibition of CDK4/6 Promotes CD8 T-cell Memory Formation. In Cancer discovery, 11, 2564-2581. doi:10.1158/2159-8290.CD-20-1540. https://pubmed.ncbi.nlm.nih.gov/33941591/

4. Vasilevsky, Nicole A, Ruby, Carl E, Hurlin, Peter J, Weinberg, Andrew D. 2011. OX40 engagement stabilizes Mxd4 and Mnt protein levels in antigen-stimulated T cells leading to an increase in cell survival. In European journal of immunology, 41, 1024-34. doi:10.1002/eji.201040449. https://pubmed.ncbi.nlm.nih.gov/21400495/

5. Boros, Katalin, Lacaud, Georges, Kouskoff, Valerie. 2011. The transcription factor Mxd4 controls the proliferation of the first blood precursors at the onset of hematopoietic development in vitro. In Experimental hematology, 39, 1090-100. doi:10.1016/j.exphem.2011.07.007. https://pubmed.ncbi.nlm.nih.gov/21782766/

6. Prochownik, Edward V, Wang, Huabo. 2022. Normal and Neoplastic Growth Suppression by the Extended Myc Network. In Cells, 11, . doi:10.3390/cells11040747. https://pubmed.ncbi.nlm.nih.gov/35203395/