Npas2, encoding the neuronal PAS domain protein 2, is a core component of the molecular clockwork. It binds with DNA at E-box sequences, forms heterodimers with BMAL1, and acts as a pyridine nucleotide-dependent and gas-responsive CO-dependent transcription factor. Its expression fluctuates with circadian rhythmicity, regulating metabolic pathways, being crucial for the central nervous system function in mammals, and involved in processes like cardiovascular function, wound healing, and carcinogenesis [1,3]. Genetic models, such as gene knockout (KO) mice, are valuable for studying Npas2 functions.

In KO mouse models, loss of Npas2 decreased CYP1A2 expression and its rhythmicity in the liver, as well as down-regulated the enzymatic activity of CYP1A2 and abrogated its time-dependency, indicating Npas2 is a key transcriptional regulator of diurnal expression of hepatic CYP1A2 [6]. In Npas2 null mutant mice, they exhibited less anxiety-like behavior than wild-type littermates, and NPAS2 was found to regulate GABAergic neurotransmission in the ventral striatum by targeting Gabra genes [7]. In lung adenocarcinoma, depletion of Npas2 in cells increased susceptibility to cisplatin treatment, as NPAS2 may enhance DNA damage repair by binding to H2AX mRNA [2]. In prostate cancer, knockdown of Npas2 inhibited cell proliferation, promoted apoptosis, and suppressed tumor growth, as it increased HIF-1A expression to enhance glycolytic metabolism [4]. Therapeutic down-regulation of Npas2 in a murine model promoted surgical skin wound healing, with faster healing, favorable mechanical strength, and less granulation tissue [5].

In conclusion, Npas2 is essential for maintaining circadian rhythms and normal physiological functions. Through model-based research, its roles in various disease areas have been revealed. In cancer, it is involved in processes like chemotherapy sensitivity, tumor growth, and glucose metabolism. In other conditions, it impacts anxiety-like behavior, wound healing, and liver enzyme regulation, highlighting its significance in understanding disease mechanisms and potential for therapeutic targeting.

References:

1. Peng, L U, Bai, Gaigai, Pang, Yingxin. . Roles of NPAS2 in circadian rhythm and disease. In Acta biochimica et biophysica Sinica, 53, 1257-1265. doi:10.1093/abbs/gmab105. https://pubmed.ncbi.nlm.nih.gov/34415290/

2. Zhang, Youyu, Chen, Yuqiao, Huang, Wentao, Fu, Kai, Zhuang, Wei. 2024. NPAS2 dampens chemo-sensitivity of lung adenocarcinoma cells by enhancing DNA damage repair. In Cell death & disease, 15, 101. doi:10.1038/s41419-023-06256-3. https://pubmed.ncbi.nlm.nih.gov/38291048/

3. Murgo, Emanuele, Colangelo, Tommaso, Bellet, Maria Marina, Malatesta, Francesco, Mazzoccoli, Gianluigi. 2023. Role of the Circadian Gas-Responsive Hemeprotein NPAS2 in Physiology and Pathology. In Biology, 12, . doi:10.3390/biology12101354. https://pubmed.ncbi.nlm.nih.gov/37887064/

4. Ma, Shuaijun, Chen, Yafan, Quan, Penghe, Jia, Weijing, Qin, Weijun. 2023. NPAS2 promotes aerobic glycolysis and tumor growth in prostate cancer through HIF-1A signaling. In BMC cancer, 23, 280. doi:10.1186/s12885-023-10685-w. https://pubmed.ncbi.nlm.nih.gov/36978001/

5. Shibuya, Yoichiro, Hokugo, Akishige, Okawa, Hiroko, Nishimura, Ichiro, Jarrahy, Reza. 2022. Therapeutic downregulation of neuronal PAS domain 2 (Npas2) promotes surgical skin wound healing. In eLife, 11, . doi:10.7554/eLife.71074. https://pubmed.ncbi.nlm.nih.gov/35040776/

6. He, Yiting, Cen, Haobin, Guo, Lianxia, Dong, Dong, Wu, Baojian. 2022. Circadian oscillator NPAS2 regulates diurnal expression and activity of CYP1A2 in mouse liver. In Biochemical pharmacology, 206, 115345. doi:10.1016/j.bcp.2022.115345. https://pubmed.ncbi.nlm.nih.gov/36379250/

7. Ozburn, Angela R, Kern, Joseph, Parekh, Puja K, Huang, Yanhua, McClung, Colleen A. 2017. NPAS2 Regulation of Anxiety-Like Behavior and GABAA Receptors. In Frontiers in molecular neuroscience, 10, 360. doi:10.3389/fnmol.2017.00360. https://pubmed.ncbi.nlm.nih.gov/29163035/