Cebpd, also known as CCAAT/enhancer-binding protein delta, is a transcription factor belonging to the CEBP family. It modulates diverse biological processes including inflammatory responses, cell motility, and extracellular matrix production. It is associated with multiple signaling pathways such as EGFR/PI3K, JAK-STAT, and Nrf2/HO-1, playing a crucial role in various physiological and pathological conditions [1,4,6]. Genetic models, like KO or CKO mouse models, are valuable for studying its functions.

In glioblastoma, Cebpd knockdown impaired cell invasion and growth, especially under hypoxia, as it is a key regulator of hypoxia-regulated proteins, activating the EGFR/PI3K pathway through ECM-integrin-mediated EGFR phosphorylation [1]. In NK cells engineered to express IL-21 against glioblastoma, deletion of Cebpd led to loss of cell potency, highlighting its role in enhancing anti-tumor efficacy [2]. In urothelial carcinoma, Cebpd acts as an oncogene, for example, its genomic amplification drives overexpression, which transcriptionally suppresses FBXW7 to stabilize MYC and fuel cell growth [3]. In airway smooth muscle, Cebpd knockdown altered the expression of numerous genes in response to glucocorticoids and TNFα, modulating glucocorticoid responses via IL-6 receptor signaling [4]. In hypertensive cardiac remodeling, Cebpd overexpression improved cardiac function by promoting miR-96-5p to negatively regulate IP3R expression, inhibiting oxidative stress and inflammation [5]. In ischemic stroke, knockdown of Cebpd in a rat model and primary neurons reduced neurological deficits, infarct size, and oxidative stress, as it promoted Nrf2/HO-1 pathway through CUL3 transcription [6]. In renal ischemia-reperfusion injury, inactivation of Cebpd in mice reduced macrophage accumulation by repressing hypoxia-induced FN-1 expression in renal epithelial cells [7].

In conclusion, Cebpd is a pleiotropic transcription factor with essential functions in multiple biological processes. Studies using KO/CKO mouse models have revealed its significant roles in diseases such as glioblastoma, urothelial carcinoma, ischemic stroke, and more. Understanding Cebpd functions can provide new insights into disease mechanisms and potential therapeutic targets.

References:

1. Mao, Xing-Gang, Xue, Xiao-Yan, Lv, Rui, Jiang, Xiao-Fan, Zhang, Xiang. 2023. CEBPD is a master transcriptional factor for hypoxia regulated proteins in glioblastoma and augments hypoxia induced invasion through extracellular matrix-integrin mediated EGFR/PI3K pathway. In Cell death & disease, 14, 269. doi:10.1038/s41419-023-05788-y. https://pubmed.ncbi.nlm.nih.gov/37059730/

2. Shanley, Mayra, Daher, May, Dou, Jinzhuang, Chen, Ken, Rezvani, Katayoun. . Interleukin-21 engineering enhances NK cell activity against glioblastoma via CEBPD. In Cancer cell, 42, 1450-1466.e11. doi:10.1016/j.ccell.2024.07.007. https://pubmed.ncbi.nlm.nih.gov/39137729/

3. Chan, Ti-Chun, Shiue, Yow-Ling, Li, Chien-Feng. 2023. The biological impacts of CEBPD on urothelial carcinoma development and progression. In Frontiers in oncology, 13, 1123776. doi:10.3389/fonc.2023.1123776. https://pubmed.ncbi.nlm.nih.gov/36776299/

4. Kan, Mengyuan, Sun, Maoyun, Jiang, Xiaofeng, Lu, Quan, Himes, Blanca E. 2022. CEBPD modulates the airway smooth muscle transcriptomic response to glucocorticoids. In Respiratory research, 23, 193. doi:10.1186/s12931-022-02119-1. https://pubmed.ncbi.nlm.nih.gov/35902923/

5. Zhao, Jinghong, Hu, Jilin, Zhang, Rongyi, Deng, Jianping. 2023. CEBPD REGULATES OXIDATIVE STRESS AND INFLAMMATORY RESPONSES IN HYPERTENSIVE CARDIAC REMODELING. In Shock (Augusta, Ga.), 60, 713-723. doi:10.1097/SHK.0000000000002228. https://pubmed.ncbi.nlm.nih.gov/37752084/

6. Chen, Nan, Xu, Yuanqi, Liu, Yushuang, Liu, Ruijia, Zhang, Zhongling. 2024. CEBPD aggravates apoptosis and oxidative stress of neuron after ischemic stroke by Nrf2/HO-1 pathway. In Experimental cell research, 440, 114127. doi:10.1016/j.yexcr.2024.114127. https://pubmed.ncbi.nlm.nih.gov/38857839/

7. Chang, Shen-Shin, Cheng, Chao-Chun, Chen, Ying-Ren, Cheng, Ya-Min, Wang, Ju-Ming. 2024. Epithelial CEBPD activates fibronectin and enhances macrophage adhesion in renal ischemia-reperfusion injury. In Cell death discovery, 10, 328. doi:10.1038/s41420-024-02082-4. https://pubmed.ncbi.nlm.nih.gov/39025831/