Clock, short for Circadian Locomotor Output Cycles Kaput, is a core circadian clock gene. It is fundamental in regulating the circadian rhythm and mediates multiple biological processes. The circadian mechanisms involving Clock and other core circadian genes like BMAL1, PER, and CRY are crucial for the regulation of cellular metabolism [1]. Clock is also associated with pathways related to angiogenesis, as well as brain processes such as sleep, stress, and memory [2,3].

In glioblastoma, blockade of the CLOCK-directed POSTN-TBK1 axis in mouse and patient-derived xenograft models inhibits tumor progression and angiogenesis, revealing CLOCK's role in promoting tumor angiogenesis [2]. In human mesenchymal stem cells (hMSCs), CLOCK deficiency accelerates senescence, while its overexpression rejuvenates aged hMSCs. Gene therapy with lentiviral vectors encoding CLOCK promotes cartilage regeneration and attenuates age-related articular degeneration in mice, indicating its role in counteracting stem cell decay and promoting tissue regeneration [4].

In conclusion, Clock is essential for maintaining the circadian rhythm and regulating cellular metabolism. Through gene knockout or conditional knockout mouse models, its role in diseases such as glioblastoma and age-related articular degeneration has been revealed. These findings contribute to understanding the biological functions of Clock and provide potential therapeutic targets for related diseases.

References:

1. Schrader, Lauren A, Ronnekleiv-Kelly, Sean M, Hogenesch, John B, Bradfield, Christopher A, Malecki, Kristen Mc. 2024. Circadian disruption, clock genes, and metabolic health. In The Journal of clinical investigation, 134, . doi:10.1172/JCI170998. https://pubmed.ncbi.nlm.nih.gov/39007272/

2. Pang, Lizhi, Dunterman, Madeline, Xuan, Wenjing, Heimberger, Amy B, Chen, Peiwen. 2023. Circadian regulator CLOCK promotes tumor angiogenesis in glioblastoma. In Cell reports, 42, 112127. doi:10.1016/j.celrep.2023.112127. https://pubmed.ncbi.nlm.nih.gov/36795563/

3. Bolsius, Youri G, Zurbriggen, Matias D, Kim, Jae Kyoung, Aton, Sara J, Havekes, Robbert. 2021. The role of clock genes in sleep, stress and memory. In Biochemical pharmacology, 191, 114493. doi:10.1016/j.bcp.2021.114493. https://pubmed.ncbi.nlm.nih.gov/33647263/

4. Liang, Chuqian, Liu, Zunpeng, Song, Moshi, Qu, Jing, Liu, Guang-Hui. 2020. Stabilization of heterochromatin by CLOCK promotes stem cell rejuvenation and cartilage regeneration. In Cell research, 31, 187-205. doi:10.1038/s41422-020-0385-7. https://pubmed.ncbi.nlm.nih.gov/32737416/