NPAS2 and Associated Diseases

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Overview of NPAS2

In humans, neuronal PAS domain protein 2 (NPAS2, also known as member of PAS protein 4) is a protein encoded by the NPAS2 gene. NPAS2 is a transcription factor belonging to the basic helix-loop-helix-PAS family. In the brain, both NPAS2 and CLOCK are essential proteins involved in the regulation of mammalian' circadian rhythms which are generated and maintained by NPAS2. More specifically, NPAS2 plays a critical role in activating transcription and translation of the core clock and clock-controlled genes in a manner of negative feedback loop in the suprachiasmatic nucleus, the part of the brain that regulates circadian rhythms.

NPAS2 in Disease

In the brain, diseases associated with NPAS2 include delayed sleep phase disorder and anxiety. While ectopic expression of NPAS2 is related to liver fibrosis and hepatocellular carcinoma.

  • Liver fibrosis

NPAS2 accelerates liver fibrosis (LF) via activating Hes1 in hepatic stellate cells (HSCs). Virus infection, cholestatic/biliary, and metabolic dysregulation can cause progressive LF with typical characteristics such as collagen deposition. Expression of NPAS2 is enriched in activated HSCs of the fibrotic liver. The NPAS2-knockout mice are protected against LF while overexpression of NPAS2 in the CCl4-induced fibrosis model can aggravate LF. In HSCs, NPAS2 is shown to significantly enhance LF and activate HSCs via direct transcriptional activation of Hes1 after fibrogenic injury. In NPAS2-knockout mice with CCl4-induced injury, overexpression of Hes1 can significantly increase the attenuated inflammation effect and ECM deposition. In summary, the fibrosis-promotive effect of NPAS2 is undergoing in an Hes1-mediated pathway, which can serve as an important therapeutic target for LF.

NPAS2-knockout mice are protected against CCL4-induced LF Fig.1 NPAS2-knockout mice are protected against CCL4-induced LF. (Yang, 2019)

  • Hepatocellular carcinoma

NPAS2 promotes hepatocellular carcinoma (HCC) cell survival by transactivating CDC25A. NPAS2 has proved to be a promising prognostic biomarker in colorectal and breast cancers. In HCC, upregulated NPAS2 can be observed. Knockdown of NPAS2 in HCC cells can significantly decrease tumor growth in xenograft model mice, which is reversed when using NPAS2-overexpression HCC cells. NPAS2 upregulation significantly facilitates HCC cell survival by promoting cell proliferation and inhibiting cell apoptosis via CDC25A-mediated activation of CDK2/4/6 and CDC25A-induced dephosphorylation of Bcl-2 respectively, thus overexpressed NPAS2 can predict a poor prognosis in HCC patients. Taken together, NPAS2 can serve as a potential therapeutic target in HCC patients.

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References

  1. Yang, T.; et al. NPAS2 Contributes to Liver Fibrosis by Direct Transcriptional Activation of Hes1 in Hepatic Stellate Cells. Molecular Therapy - Nucleic Acids. 2019, 18: 1009–1022.
  2. Yuan, P.; et al. NPAS2 promotes cell survival of hepatocellular carcinoma by transactivating CDC25A. Cell Death Dis. 2017, 8: e2704–e2704.
For research use only. Not intended for any clinical use.