Dusp1-KO Mouse

DUSP1, short for dual-specificity phosphatase 1, is a crucial regulator in multiple biological processes. It is involved in modulating various signaling pathways, especially those related to mitogen-activated protein kinase (MAPK) [1,2,4,6,7,8,9,10]. By regulating these pathways, DUSP1 impacts cell survival, apoptosis, inflammation, and mitochondrial function, which are essential for normal cellular homeostasis and organismal health [1,3,4,7,9]. Genetic models, such as knockout (KO) mice, have been instrumental in uncovering its functions.

In mouse models, Dusp1 gene deletion exacerbates acute ischemic injury, post-ischemic renal fibrosis, and tubular mitochondrial dysfunction in ischemic acute kidney injury (AKI). Mechanistically, DUSP1 deficiency leads to aberrant phosphorylation of JNK and BAX mitochondria translocation, promoting mitochondrial DNA (mtDNA) leakage and activating the cGAS-STING pathway [1]. In acute myeloid leukemia (AML), knockdown of DUSP1 by siRNA sensitizes AML cells to cytarabine treatments, and DUSP1 is overexpressed in NRAS mutated AML [2]. In gouty arthritis, downregulation of DUSP1 expression increases the secretion of inflammatory cytokines after MSU treatment, while overexpression has the opposite effect [3]. In THP-1 macrophages infected with attenuated Mycobacterium bovis Bacillus Calmette-Guérin (BCG), DUSP1 knockdown inhibits macrophage apoptosis and activation of MAPKs/NF-κB signaling pathway [4]. In head and neck squamous cell carcinoma, lentivirus-mediated DUSP1 knockdown in iCAF inhibits tumor cell proliferation, invasion, and migration [5]. In cervical cancer cells, overexpression of DUSP1 targets and reduces the expression of miR-21, blocking the JAK2/STAT3 signaling pathway [6]. In diabetic nephropathy, overexpression of DUSP1 interrupts Mff-related mitochondrial fission, reducing hyperglycemia-mediated mitochondrial damage [7]. In salivary gland squamous cell carcinomas, DUSP1 KO clones in A253 human cells show reduced tumor-forming ability [8]. In zebrafish, dusp1 -/- zebrafish have a narrowed temperature-survival range due to mitochondrial dysfunction [9]. In prostate cancer, a piRNA named PROPER suppresses DUSP1 translation by promoting its circularization, and inhibition of PROPER suppresses xenograft growth [10].

In conclusion, DUSP1 plays diverse and essential biological functions, mainly through its regulation of signaling pathways. The use of Dusp1 KO/CKO mouse models and other loss-of-function experiments has significantly contributed to our understanding of its role in diseases such as AKI, AML, gouty arthritis, tuberculosis, head and neck squamous cell carcinoma, cervical cancer, diabetic nephropathy, salivary gland squamous cell carcinomas, and prostate cancer. These studies provide potential therapeutic targets for treating these diseases.

References:

1. Shi, Lang, Zha, Hongchu, Pan, Zhou, Song, Zhixia, Zhu, Jiefu. 2023. DUSP1 protects against ischemic acute kidney injury through stabilizing mtDNA via interaction with JNK. In Cell death & disease, 14, 724. doi:10.1038/s41419-023-06247-4. https://pubmed.ncbi.nlm.nih.gov/37935658/

2. Sun, Huali, Ren, Yanling, Zhou, Xinping, Ying, Shenpeng, Lin, Peipei. . DUSP1 Signaling Pathway Regulates Cytarabine Sensitivity in Acute Myeloid Leukemia. In Technology in cancer research & treatment, 22, 15330338231207765. doi:10.1177/15330338231207765. https://pubmed.ncbi.nlm.nih.gov/37872685/

3. Nie, Jing, Qiu, Hongbin. . DUSP1 Mitigates MSU-Induced Immune Response in Gouty Arthritis Reinforcing Autophagy. In Frontiers in bioscience (Landmark edition), 29, 222. doi:10.31083/j.fbl2906222. https://pubmed.ncbi.nlm.nih.gov/38940057/

4. Liu, Zhanyou, Wang, Jianhong, Dai, Fan, Zhang, Dongtao, Li, Wu. 2023. DUSP1 mediates BCG induced apoptosis and inflammatory response in THP-1 cells via MAPKs/NF-κB signaling pathway. In Scientific reports, 13, 2606. doi:10.1038/s41598-023-29900-6. https://pubmed.ncbi.nlm.nih.gov/36788275/

5. Gao, Jiaxing, Wang, Zengxu, Lin, Shanfeng, Li, Zhenning, Liu, Fayu. 2024. CCR7/DUSP1 signaling Axis mediates iCAF to regulates head and neck squamous cell carcinoma growth. In Cellular signalling, 122, 111305. doi:10.1016/j.cellsig.2024.111305. https://pubmed.ncbi.nlm.nih.gov/39067836/

6. Chen, Hailin, Ren, Songsen, Wan, Hui, Luo, Yi, Cai, Meiling. 2023. DUSP1 regulates the JAK2/STAT3 signaling pathway through targeting miR-21 in cervical cancer cells. In Cellular and molecular biology (Noisy-le-Grand, France), 69, 40-44. doi:10.14715/cmb/2023.69.8.6. https://pubmed.ncbi.nlm.nih.gov/37715430/

7. Sheng, Junqin, Li, Hongyan, Dai, Qin, Zhang, Jisheng, Feng, Jianxun. 2018. DUSP1 recuses diabetic nephropathy via repressing JNK-Mff-mitochondrial fission pathways. In Journal of cellular physiology, 234, 3043-3057. doi:10.1002/jcp.27124. https://pubmed.ncbi.nlm.nih.gov/30191967/

8. Acero-Riaguas, Lucía, Griso-Acevedo, Ana Belén, SanLorenzo-Vaquero, Alejandro, Sastre, Leandro, Sastre-Perona, Ana. 2024. DUSP1 and SOX2 expression determine squamous cell carcinoma of the salivary gland progression. In Scientific reports, 14, 15007. doi:10.1038/s41598-024-65945-x. https://pubmed.ncbi.nlm.nih.gov/38951654/

9. Wang, Ying, Wang, Hua-Min, Zhou, Yan, Hu, Peng, Chen, Liang-Biao. . Dusp1 regulates thermal tolerance limits in zebrafish by maintaining mitochondrial integrity. In Zoological research, 44, 126-141. doi:10.24272/j.issn.2095-8137.2022.397. https://pubmed.ncbi.nlm.nih.gov/36419379/

10. Ben, Shuai, Ding, Zhutao, Xin, Junyi, Cheng, Gong, Wang, Meilin. 2024. piRNA PROPER Suppresses DUSP1 Translation by Targeting N6-Methyladenosine-Mediated RNA Circularization to Promote Oncogenesis of Prostate Cancer. In Advanced science (Weinheim, Baden-Wurttemberg, Germany), 11, e2402954. doi:10.1002/advs.202402954. https://pubmed.ncbi.nlm.nih.gov/38962952/