Per2, short for Period2, is a core component of the circadian rhythm, playing a crucial role in regulating the circadian rhythm of the biological clock [3]. It is involved in various physiological systems such as metabolism, sleep, body temperature, and immune function [4].

In oral squamous cell carcinoma, PER2 expression was reduced. In vitro and in vivo experiments demonstrated that PER2 inhibited PD-L1 expression and enhanced T-cell-mediated OSCC cell killing by suppressing the IKK/NF-κB pathway [1].

In pituitary adenomas, PER2 is prominently upregulated. Jetlagged mice with PER2 upregulation have accelerated growth of GH3 xenograft tumor, while loss of Per2 protects mice against developing estrogen-induced pituitary adenoma, and RNA-seq analysis suggests its involvement in cell cycle disturbance in pituitary adenoma regulation [2].

In ameloblast differentiation, circadian disruption mice showed downregulated PER2 expression along with reduced amelogenin expression and enamel matrix secretion. Per2 knockdown in ameloblast-lineage cells decreased amelogenin and related protein expressions, inhibited mineralization, while overexpression of PPARγ partially reversed these results, indicating PER2's role in enamel formation through the PPARγ/AKT1/β-catenin axis [5].

In LPS-induced chondrocyte injury, Per2 levels were reduced, and overexpression of Per2 increased cell proliferation, inhibited apoptosis and inflammation, and activated the PTEN/PI3K/Akt signalling pathway [6].

In ulcerative colitis, PER2 was decreased in inflamed mucosa and peripheral blood CD4+ T cells of patients. Overexpression of PER2 in UC CD4+ T cells inhibited IFN-γ production by down-regulating ADAM12 expression [7].

In spatial working memory of mice, Per2 knockout mice exhibited impaired memory, with higher levels of dopamine-related proteins DRD1, PKA, and CREB, and treatment with DRD1 antagonist recovered their memory function [8].

In conclusion, Per2 is essential for regulating the circadian rhythm and has significant impacts on multiple biological processes and disease conditions. Gene knockout mouse models, like Per2 KO mice, have been instrumental in revealing its roles in diseases such as oral squamous cell carcinoma, pituitary adenomas, ulcerative colitis, and in processes like ameloblast differentiation, chondrocyte injury response, and spatial working memory regulation.

References:

1. Zhang, Zhiwei, Sun, Deping, Tang, Hong, Yin, Shilin, Yang, Kai. . PER2 binding to HSP90 enhances immune response against oral squamous cell carcinoma by inhibiting IKK/NF-κB pathway and PD-L1 expression. In Journal for immunotherapy of cancer, 11, . doi:10.1136/jitc-2023-007627. https://pubmed.ncbi.nlm.nih.gov/37914384/

2. Guo, Lianxia, Cen, Haobin, Weng, Jiaxian, Chen, Zhiyong, Wu, Baojian. 2023. PER2 integrates circadian disruption and pituitary tumorigenesis. In Theranostics, 13, 2657-2672. doi:10.7150/thno.82995. https://pubmed.ncbi.nlm.nih.gov/37215573/

3. Jiang, Huihui, Yang, Xin, Mi, Miaomiao, Xin, Yu, Sun, Chengming. 2021. PER2: a potential molecular marker for hematological malignancies. In Molecular biology reports, 48, 7587-7595. doi:10.1007/s11033-021-06751-w. https://pubmed.ncbi.nlm.nih.gov/34642831/

4. Pavithra, S, Aich, Adrija, Chanda, Adrita, Gawade, Pranotee, Das, Raunak Kumar. 2023. PER2 gene and its association with sleep-related disorders: A review. In Physiology & behavior, 273, 114411. doi:10.1016/j.physbeh.2023.114411. https://pubmed.ncbi.nlm.nih.gov/37981094/

5. Huang, Wushuang, Zheng, Xueqing, Yang, Mei, Li, Ruiqi, Song, Yaling. 2021. PER2-mediated ameloblast differentiation via PPARγ/AKT1/β-catenin axis. In International journal of oral science, 13, 16. doi:10.1038/s41368-021-00123-7. https://pubmed.ncbi.nlm.nih.gov/34011974/

6. Zhao, Yu, Ma, Ding, Dong, Bingchen, Li, Ming. . Per2 attenuates LPS-induced chondrocyte injury through the PTEN/PI3K/Akt signalling pathway. In Bioscience reports, 40, . doi:10.1042/BSR20200417. https://pubmed.ncbi.nlm.nih.gov/32426819/

7. Ye, Yulan, Liu, Changqin, Wu, Ruijin, Liu, Zhanju, Chen, Liang. 2024. Circadian clock component PER2 negatively regulates CD4+ T cell IFN-γ production in ulcerative colitis. In Mucosal immunology, 17, 1161-1173. doi:10.1016/j.mucimm.2024.07.010. https://pubmed.ncbi.nlm.nih.gov/39097147/

8. Kim, Mikyung, Custodio, Raly James, Lee, Hyun Jun, Kim, Hee Jin, Cheong, Jae Hoon. 2022. Per2 Expression Regulates the Spatial Working Memory of Mice through DRD1-PKA-CREB Signaling. In Molecular neurobiology, 59, 4292-4303. doi:10.1007/s12035-022-02845-z. https://pubmed.ncbi.nlm.nih.gov/35508866/