Alternative titles; symbols
HGNC Approved Gene Symbol: GNL3
Cytogenetic location: 3p21.1 Genomic coordinates (GRCh38): 3:52,685,920-52,694,497 (from NCBI)
Using a cDNA subtractive screen in rat CNS stem cells, Tsai and McKay (2002) identified a novel cDNA with preferential expression in stem cells. They designated the encoded protein nucleostemin because of its nucleolar localization. They cloned a full-length mouse homolog and, by database searching, identified the human homolog, which had been isolated based on its estrogen-induced increased expression in breast cancer cell lines (Charpentier et al., 2000). The mouse and rat proteins share 90% sequence identity, and the 549-amino acid human protein shares 81% sequence identity with the rat protein. The NS protein contains 2 GTP-binding motifs, an N-terminal basic domain, and a C-terminal acidic domain.
By immunohistochemical and electron microscopic analysis of nontumor rodent and human cells, Politz et al. (2005) found that nucleostemin localized to nucleolar subregions deficient in rRNA.
Tsai and McKay (2002) found that when stem cells differentiate, nucleostemin expression decreases rapidly prior to cell cycle exit both in vitro and in vivo. The protein was not found in the differentiated cells of adult tissue, suggesting a role in maintaining stem cell self-renewal. Depletion or overexpression of nucleostemin reduces cell proliferation in CNS stem cells and transformed cells. Mutation analysis indicated that excessive nucleostemin, particularly mutants lacking the GTP-regulatory domain, prevents cells from entering mitosis and causes apoptosis in a p53 (191170)-dependent manner. The N-terminal basic domain mediates the interaction with p53 and is required for the cell death caused by overexpression.
Using human cell lines, Dai et al. (2008) showed that both aberrantly high and low levels of NS activated p53 and induced G1 cell cycle arrest. Overexpressed NS interacted directly with and inhibited MDM2 (164785), an E3 ubiquitin ligase that ubiquitinates p53 and targets it for proteasome-mediated degradation. Conversely, knockdown of NS via small interfering RNA caused cell stress that resulted in p53 activation due to sequestration and inhibition of MDM2 by binding of MDM2 with the ribosomal proteins L5 (RPL5; 603634) and L11 (RPL11; 604175). Coimmunoprecipitation and domain analysis revealed that the coiled-coil domain of NS directly interacted with the central acidic domain of MDM2. A ternary complex of p53, MDM2, and NS formed when all 3 proteins were coexpressed.
Hartz (2012) mapped the GNL3 gene to chromosome 3p21.1 based on an alignment of the GNL3 sequence (GenBank AF191018) with the genomic sequence (GRCh37).
Charpentier, A. H., Bednarek, A. K., Daniel, R. L., Hawkins, K. A., Laflin, K. J., Gaddis, S., MacLeod, M. C., Aldaz, C. M. Effects of estrogen on global gene expression: identification of novel targets of estrogen action. Cancer Res. 60: 5977-5983, 2000. [PubMed: 11085516]
Dai, M.-S., Sun, X.-X., Lu, H. Aberrant expression of nucleostemin activates p53 and induces cell cycle arrest via inhibition of MDM2. Molec. Cell. Biol. 28: 4365-4376, 2008. [PubMed: 18426907] [Full Text: https://doi.org/10.1128/MCB.01662-07]
Hartz, P. A. Personal Communication. Baltimore, Md. 6/29/2012.
Politz, J. C. R., Polena, I., Trask, I., Bazett-Jones, D. P., Pederson, T. A nonribosomal landscape in the nucleolus revealed by the stem cell protein nucleostemin. Molec. Biol. Cell 16: :-3401-3410, 2005.
Tsai, R. Y. L., McKay, R. D. G. A nucleolar mechanism controlling cell proliferation in stem cells and cancer cells. Genes Dev. 16: 2991-3003, 2002. [PubMed: 12464630] [Full Text: https://doi.org/10.1101/gad.55671]