Alternative titles; symbols
HGNC Approved Gene Symbol: TRIM63
Cytogenetic location: 1p36.11 Genomic coordinates (GRCh38): 1:26,051,301-26,067,630 (from NCBI)
The RING finger motif is a distinct zinc-chelating domain involved in mediating protein-DNA and protein-protein interactions. RING finger proteins, including RNF28, are involved in a variety of functions such as oncogenesis, signal transduction, peroxisome biogenesis, viral infection, development, transcriptional repression, and ubiquitination (summary by Dai and Liew, 2001).
By searching a human heart EST database and performing 5-prime RACE, Dai and Liew (2001) cloned a full-length RNF28 cDNA, which they called SMRZ, encoding a 288-amino acid protein with an N-terminal RING domain, also known as the C3HC4-type zinc finger domain. Northern blot analysis detected an approximately 2.1-kb RNF28 transcript exclusively in heart and skeletal muscle, with higher expression in fetal than in adult heart, suggesting that RNF28 is developmentally regulated. A yeast 2-hybrid screen demonstrated that the RING domain of RNF28 is responsible for protein-protein interaction. Dai and Liew (2001) determined that RNF28 interacts with SMT3B (SMT3H2; 603042), a member of the ubiquitin-like gene family. Transient transfection of RNF28 into C2C12 myoblasts localized RNF28 to the nucleus. Dai and Liew (2001) suggested that RNF28 may be involved in the cell cycle regulatory process of striated muscle cells.
Independently, Centner et al. (2001) cloned and characterized 3 members of the RING finger family, which they designated MURF1 (RNF28), MURF2 (RNF29; 606469), and MURF3 (RNF30; 606474). RNF28 shares 62% and 77% sequence homology with RNF29 and RNF30, respectively. All 3 proteins share a conserved N-terminal RING domain and zinc-binding B-box motif as well as 2 coiled-coil dimerization motif boxes in their central regions. In vitro, they form dimers/heterodimers by shared coiled-coil motifs. Dot-blot analysis demonstrated muscle-specific expression of RNF28 and RNF30, but low-level expression of RNF29 in liver in addition to expression in striated muscle. RNF28 is expressed in all striated muscle tissues throughout development.
Centner et al. (2001) found that RNF28 binds in vitro to the titin repeats A168/A169 adjacent to the titin kinase domain. In myofibrils, RNF28 is present within the periphery of the M-line lattice in close proximity to the catalytic kinase domain of titin, within the Z line lattice, and also in soluble form within the cytoplasm.
By radiation hybrid analysis, Centner et al. (2001) mapped the RNF28 gene to chromosome 1p33-p31.1. By FISH, Dai and Liew (2001) mapped the RNF28 gene to chromosome 1p34-p33.
To identify candidate molecular mediators of muscle atrophy, Bodine et al. (2001) performed transcript profiling. Although many genes were upregulated in a single rat model of atrophy, only a small subset was universal in all atrophy models (denervation, immobilization, and unweighting). Two of these genes encode ubiquitin ligases: MURF1, and a gene designated 'muscle atrophy F-box' (MAFBX; 606604). Bodine et al. (2001) generated mice deficient in Murf1 by targeted disruption. Murf1 -/- mice were viable and fertile and appeared normal. They had normal growth curves relative to those of wildtype littermates, and skeletal muscles and heart muscle had normal weights and morphology. After denervation, Murf1 -/- mice had significant muscle sparing relative to wildtype littermates at 14 days but not at 7 days. Bodine et al. (2001) demonstrated that MURF1 is a ubiquitin ligase and that it is expressed selectively in cardiac and skeletal muscle.
Cai et al. (2004) created transgenic mice with nuclear factor kappa-B (NFKB; see 164011) either activated or inhibited selectively in skeletal muscle through expression of constitutively active I-kappa-B kinase-beta (IKKB; 603258) or a dominant inhibitory form of I-kappa-B-alpha (IKBA; 164008), respectively. They referred to these mice as MIKK (muscle-specific expression of IKKB) or MISR (muscle-specific expression of IKBA superrepressor), respectively. MIKK mice showed profound muscle wasting that resembled clinical cachexia, whereas MISR mice showed no overt phenotype. Muscle loss in MIKK mice was due to accelerated protein breakdown through ubiquitin-dependent proteolysis. Expression of the E3 ligase Murf1, a mediator of muscle atrophy, was increased in MIKK mice. Pharmacologic or genetic inhibition of the Ikkb/Nfkb/Murf1 pathway in MIKK mice reversed the muscle atrophy. The Nfkb inhibition in MISR mice substantially reduced denervation- and tumor-induced muscle loss and improved survival rates. The results were consistent with a critical role for NFKB in the pathology of muscle wasting and established NFKB as an important clinical target for the treatment of muscle atrophy.
Lin et al. (2009) found that the hypertrophic response of rat cardiomyocytes to isoproterenol or aldosterone required a pathway that included calcineurin (see 114105), Nfatc3 (602698), microRNA-23a (MIR23A; 607962), and Murf1. Nfatc3 directly upregulated expression of Mir23a, and elevated Mir23a levels inhibited Murf1 mRNA translation by binding to the 3-prime UTR of the Murf1 transcript. Knockdown of any of these components abrogated the hypertrophic response of cardiomyocytes to aldosterone or isoproterenol.
Willis et al. (2009) generated transgenic mice expressing increased amounts of cardiac Murf1 and observed nonprogressive thinning of the left ventricular wall and a concomitant decrease in cardiac function in adult transgenic mice. Experimental induction of cardiac hypertrophy by transaortic constriction (TAC) induced rapid failure of Murf1-transgenic hearts with development of eccentric hypertrophy. Microarray analysis demonstrated alterations in levels of genes associated with metabolism, particularly mitochondrial processes, in transgenic hearts, both at baseline and during the development of hypertrophy. ATP levels in Murf1-transgenic mice did not differ from wildtype despite depressed contractility following TAC, and creatine kinase (CK; 123310) and CKMB levels were unaffected in Murf1-transgenic hearts; however, total CK activity was significantly inhibited. Willis et al. (2009) concluded that MURF1 plays a role in the regulation of cardiac energetics in vivo.
Bodine, S. C., Latres, E., Baumhueter, S., Lai, V. K.-M., Nunez, L., Clarke, B. A., Poueymirou, W. T., Panaro, F. J., Na, E., Dharmarajan, K., Pan, Z.-Q., Valenzuela, D. M., DeChiara, T. M., Stitt, T. N., Yancopoulos, G. D., Glass, D. J. Identification of ubiquitin ligases required for skeletal muscle atrophy. Science 294: 1704-1708, 2001. [PubMed: 11679633] [Full Text: https://doi.org/10.1126/science.1065874]
Cai, D., Frantz, J. D., Tawa, N. E., Jr., Melendez, P. A., Oh, B.-C., Lidov, H. G. W., Hasselgren, P.-O., Frontera, W. R., Lee, J., Glass, D. J., Shoelson, S. E. IKK-beta/NF-kappa-B activation causes severe muscle wasting in mice. Cell 119: 285-298, 2004. [PubMed: 15479644] [Full Text: https://doi.org/10.1016/j.cell.2004.09.027]
Centner, T., Yano, J., Kimura, E., McElhinny, A. S., Pelin, K., Witt, C. C., Bang, M.-L., Trombitas, K., Granzier, H., Gregorio, C. C., Sorimachi, H., Labeit, S. Identification of muscle specific ring finger proteins as potential regulators of the titin kinase domain. J. Molec. Biol. 306: 717-726, 2001. [PubMed: 11243782] [Full Text: https://doi.org/10.1006/jmbi.2001.4448]
Dai, K.-S., Liew, C.-C. A novel human striated muscle RING zinc finger protein, SMRZ, interacts with SMT3b via its RING domain. J. Biol. Chem. 276: 23992-23999, 2001. [PubMed: 11283016] [Full Text: https://doi.org/10.1074/jbc.M011208200]
Lin, Z., Murtaza, I., Wang, K., Jiao, J., Gao, J., Li, P.-F. miR-23a functions downstream of NFATc3 to regulate cardiac hypertrophy. Proc. Nat. Acad. Sci. 106: 12103-12108, 2009. [PubMed: 19574461] [Full Text: https://doi.org/10.1073/pnas.0811371106]
Willis, M. S., Schisler, J. C., Li, L., Rodriguez, J. E., Hilliard, E. G., Charles, P. C., Patterson, C. Cardiac muscle ring finger-1 increases susceptibility to heart failure in vivo. Circ. Res. 105: 80-88, 2009. [PubMed: 19498199] [Full Text: https://doi.org/10.1161/CIRCRESAHA.109.194928]