Alternative titles; symbols
HGNC Approved Gene Symbol: USP28
Cytogenetic location: 11q23.2 Genomic coordinates (GRCh38) : 11:113,797,875-113,875,572 (from NCBI)
The ubiquitin-dependent protein degradation pathway is essential for proteolysis of intracellular proteins and peptides. Enzymes that remove ubiquitin from ubiquitin-conjugated peptides, like USP28, affect the fate and degradation of intracellular proteins and are essential for maintenance of cell-free ubiquitin pools (Valero et al., 2001).
By sequencing clones obtained from a size-fractionated fetal brain cDNA library, Nagase et al. (2000) cloned USP28, which they designated KIAA1515. The transcript contains repetitive elements in its 5-prime and 3-prime regions, and the deduced protein contains a ubiquitin C-terminal hydrolase domain and a tetratricopeptide domain. RT-PCR ELISA detected moderate to high expression in all adult and fetal tissues and adult brain regions examined, with highest expression in adult heart, brain, and skeletal muscle.
By searching databases for USP-like sequences, followed by RT-PCR of several cDNA libraries and 5-prime RACE of a kidney cDNA library, Valero et al. (2001) cloned full-length USP28. The deduced 1,077-amino acid protein has a calculated molecular mass of 122.4 kD and shares 51.4% identity with USP25 (604736). Northern blot analysis detected highest expression of a 4.5-kb transcript in heart and skeletal muscle, with lower expression in all other tissues examined. RT-PCR detected a second USP28 transcript that was restricted to adult and fetal muscle, heart, and brain. This transcript contains an extra exon, 19A, that introduces 62 codons into the open reading frame.
Valero et al. (2001) showed that recombinant USP28 cleaved ubiquitin from a test protein.
The CHK2 (CHEK2; 604373)-p53 (TP53; 191170)-PUMA (BBC3; 605854) pathway is a major regulator of DNA damage-induced apoptosis. Using mass spectrometry, Zhang et al. (2006) found that endogenous USP28, but not USP25 or USP7 (602519), interacted with transfected 53BP1 (TP53BP1; 605230) in HeLa cells. In a human lung carcinoma cell line that recapitulated the CHK2-p53-PUMA pathway, USP28 was required to stabilize CHK2 and 53BP1 in response to DNA damage. Both USP28 and CHK2 were required for DNA damage-induced apoptosis, and they accomplished this in part through regulation of p53 induction of proapoptotic genes like PUMA. A catalytically-inactive version of USP28, in which the catalytic cysteine (cys171) was changed to alanine, rendered cells resistant to irradiation-induced killing and apoptosis.
Using an RNA interference screen in HEK293T cells, Saei et al. (2018) identified USP28 as a negative regulator of MAPK signaling. USP28 overexpression and depletion experiments demonstrated that ubiquitination and stability of BRAF (164757) were directly regulated through interplay between the FBW7 (FBXW7; 606278)/SCF ubiquitin ligase complex and USP28, leading to enhanced MAPK activity. The authors found that USP28 was deleted in a proportion of melanoma patients. Analysis of melanoma cell lines showed that loss of USP28 enhanced BRAF stabilization and impaired apoptosis induced by the BRAF inhibitor vemurafenib. Furthermore, USP28 mediated vemurafenib sensitivity in vivo, as demonstrated by vemurafenib treatment of immunodeficient mice injected with USP28-depleted human melanoma cells. The authors identified the PLK1 (602098) inhibitor rigosertib as a compound that selectively impaired the viability of USP28-depleted cells.
Valero et al. (2001) determined that the USP28 gene contains 26 exons, including the alternatively spliced exon 19A.
By radiation hybrid analysis, Nagase et al. (2000) mapped the USP28 gene to chromosome 11. Valero et al. (2001) mapped the USP28 gene to chromosome 11q23 by genomic sequence analysis.
Nagase, T., Kikuno, R., Ishikawa, K., Hirosawa, M., Ohara, O. Prediction of the coding sequences of unidentified human genes. XVII. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro. DNA Res. 7: 143-150, 2000. [PubMed: 10819331] [Full Text: https://doi.org/10.1093/dnares/7.2.143]
Saei, A., Palafox, M., Benoukraf, T., Kumari, N., Jaynes, P. W., Iyengar, P. V., Munoz-Couselo, E., Nuciforo, P., Cortes, J., Notzel, C., Kumarakulasinghe, N. B., Richard, J. L. C., Isa, Z. F. B. A., Pang, B., Guzman, M., Siqin, Z., Yang, H., Tam, W. L., Serra, V., Eichhorn, P. J. A. Loss of USP28-mediated BRAF degradation drives resistance to RAF cancer therapies. J. Exp. Med. 215: 1913-1928, 2018. [PubMed: 29880484] [Full Text: https://doi.org/10.1084/jem.20171960]
Valero, R., Bayes, M., Sanchez-Font, M. F., Gonzalez-Angulo, O., Gonzalez-Duarte, R., Marfany, G. Characterization of alternatively spliced products and tissue-specific isoforms of USP28 and USP25. Genome Biol. 2: research0043, 2001. Note: Electronic Article. [PubMed: 11597335] [Full Text: https://doi.org/10.1186/gb-2001-2-10-research0043]
Zhang, D., Zaugg, K., Mak, T. W., Elledge, S. J. A role for the deubiquitinating enzyme USP28 in control of the DNA-damage response. Cell 126: 529-542, 2006. [PubMed: 16901786] [Full Text: https://doi.org/10.1016/j.cell.2006.06.039]