NUP98 and Associated Diseases
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Overview of NUP98
In humans, nuclear pore complex protein NUP98-NUP96 (NUP98, also known as nucleoporin 98 and 96 precursor) is a protein encoded by the NUP98 gene. The nucleoporin gene family member NUP98 encodes a 186 kDa precursor protein that is cleaved into a 98 kDa and a 96 kDa nucleoporin by autoproteolysis. The Gly-Leu-Phe-Gly (GLGF) repeat domain-contained 98 kDa nucleoporin is involved in several cellular functions, including nuclear import, nuclear export, mitotic progression, and gene expression regulation. The 96 kDa nucleoporin is a structural component of the nuclear pore complexes, which controls the movement of macromolecules between the nucleus and cytoplasm and is made up of several polypeptide subunits from the nucleoporin family.
NUP98 in Disease
Diseases with ectopic expression of NUP98 contain acute myelogenous leukemia and cancers such as hepatocellular carcinomas.
- Acute myelogenous leukemia
Abnormal expression of NUP98 is related to acute myelogenous leukemia (AML). The formation of NUP98 fusion protein caused by chromosomal translocations is associated with AML. NUP98 can interact with RAE1, whose depletion causes aneuploidy and further enhances tumorigenesis. RAE1 expression and localization are disturbed and severe chromosomal segregation abnormalities are caused by NUP98 knockdown. Overexpression of exogenous NUP98 fusion protein can robustly reduce RAE1 expression in leukemia cell line K562. Reduced RAE1 expression is also observed in the spleen of transgenic mice and the bone marrow of AML patients expressing NUP98 fusion protein. In conclusion, NUP98/RAE1 axis may provide a novel strategy for AML therapy.
- Hepatocellular carcinomas
NUP98/p21 axis is linked to the progression of hepatocellular carcinomas (HCC). As a well-known tumor suppressor, p53 utilizes different mechanisms to regulate its myriad target genes. According to the consequence of conventional and single-molecule mRNA analyses, NUP98 is required for full expression of p21 which is a critical effector of the p53 pathway. The siRNA-based knockdown of NUP98 can decrease the expression of p21 in a posttranscriptional mechanism where NUP98 can protect p21 from degradation by the exosome. In human HCC patients, NUP98 expression is decreased and coincides with p21 expression. Conclude, an unrecognized function of NUP98 is recognized, which expands the therapeutic strategies for HCC.
Fig.1 Knockdown of NUP98 can reduce p21 expression when the p53 signal pathway is activated. (Singer, 2012)
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References
- Funasaka, T.; et al. RNA export factor RAE1 contributes to NUP98-HOXA9-mediated leukemogenesis. Cell Cycle. 2011, 10: 1456–1467.
- Singer, S.; et al. Nuclear Pore Component Nup98 Is a Potential Tumor Suppressor and Regulates Posttranscriptional Expression of Select p53 Target Genes. Molecular Cell. 2012, 48: 799–810.
