NPAS2

Official Full Name

neuronal PAS domain protein 2

Organism

Homo sapiens

GeneID

4862

Background

The protein encoded by this gene is a member of the basic helix-loop-helix (bHLH)-PAS family of transcription factors. A similar mouse protein may play a regulatory role in the acquisition of specific types of memory. It also may function as a part of a molecular clock operative in the mammalian forebrain. [provided by RefSeq, Jul 2008]

Synonyms

MOP4; PASD4; bHLHe9;

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Detailed Information

NPAS2 (neuronal PAS domain protein 2) was discovered during the early development of the mouse brain and is the largest clock gene in humans. NPAS2, also known as MOP4, is a gene necessary for the body to maintain normal biological rhythms and participates in the regulation of the biological clock. It also plays an important role in many aspects such as cell growth, differentiation and apoptosis, tumor growth inhibition, and may be a new tumor suppressor gene.

Expression and Distribution of NPAS2

NPAS2 is widely expressed and distributed in humans. Studies have confirmed that NPAS2 exists not only in the earliest discovered brain, but also in almost all human tissues except testes. It is mainly distributed in the central rhythm system in the biological rhythm center. The formation of human biological rhythms depends on the normal expression of NPAS2. Studies have found that when NPAS2 is abnormally expressed, the incidence of circadian rhythm-related diseases such as hypertension, metabolic syndrome, tumors, and cardiovascular and cerebrovascular diseases may increase. Studies have suggested that abnormal expression of the circadian clock gene may be one of the risk factors for metabolic syndrome, and pointed out that NPAS2 and its isomer NPAS2-rs11541353 are related to the development of hypertension, and its allele is a protective factor for the development of hypertension.

In addition, studies have found abnormal expression of NPAS2 in tumor tissues. The high expression of NPAS2 can improve the survival rate of breast cancer patients. It is related to the prognosis of breast cancer. By extracting DNA from breast cancer tissues, TaqMan allele analysis method was used to analyze the NPAS2 genotype, and the correlation with clinical pathological results was done. It is found that the high expression of NPAS2 is closely related to the tumor-free survival and overall survival rate of patients, and it is proposed that NPAS2 is expected to become a new sensitive indicator for judging the prognosis of breast cancer. Studies have found that functional NPAS2 can improve the sensitivity of non-Hodgkin's lymphoma (NHL), and NPAS2 may become a new tumor marker for NHL. After testing more than ten other circadian clock genes, it was found that NPAS2 is the most closely related to the occurrence of prostate cancer.

NPAS2 Figure 1. Representation of the circadian clock network. (Yang, S., et al. 2017)

NPAS2 Regulates Biological Rhythm

The NPAS/BMAL1 heterodimer formed by NPAS2 and BMAL1, combined with the target gene promoter E-box, can regulate the expression of the other two circadian clock genes Per and Cry, and play a role in regulating the circadian clock rhythm. Therefore, NPAS2 may be a gene necessary for the body to maintain normal biological rhythms. When it is mutated or deleted, it will cause disturbances in the biological rhythm system. The homology of CLOCK and NPAS2 results in functional similarity and overlap between the two. The study found that mice lacking BMAL1 completely lost circadian rhythm, while individuals with CLOCK mutations did not show severe symptoms, which may be due to the replacement of its effect by the homologous analogue of CLOCK NPAS2.

NPAS2 and Tumors

Tumor development involves cell damage, apoptosis, DNA damage repair and other processes, and the NPAS2 gene may be related to these processes. NPAS2 can affect tumor formation and growth through tumor-related biological pathways. In addition, NPAS2 is also involved in the DNA damage repair response. NPAS2 is related to cell injury and apoptosis-related heat shock protein 90 (HSP90) and the role of polycyclic aromatic hydrocarbon (AH) receptors. The AH receptor plays the most critical role by its second bHLHPAS structure, while NPAS2 has a bHLH-PAS domain similar to that in hypoxia-inducible factor (HIF) and endothelial cell PAS domain protein (EPAS) 1. It may activate mammalian gene expression in response to hypoxia, which may be related to cell hypoxia damage and apoptosis.

References:

Yang, S. , Ren, Q. , Wen, L. , Hu, J. , & Wang, H. . (2017). Research progress on circadian clock genes in common abdominal malignant tumors (review). Oncology Letters.
Yuan, P. , Li, J. , Zhou, F. , Huang, Q. , Zhang, J. , & Guo, X. , et al. (2017). Npas2 promotes cell survival of hepatocellular carcinoma by transactivating cdc25a. Cell Death and Disease,8(3), e2704.
Ozburn, A. R. , Joseph, K. , Parekh, P. K. , Logan, R. W. , Zheng, L. , & Edgardo, F. , et al. (2017). Npas2 regulation of anxiety-like behavior and gabaa receptors. Frontiers in Molecular Neuroscience, 10, 360.

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