Alternative titles; symbols
HGNC Approved Gene Symbol: RB1CC1
Cytogenetic location: 8q11.23 Genomic coordinates (GRCh38) : 8:52,622,458-52,714,435 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 8q11.23 | Breast cancer, somatic | 114480 | 3 |
RB1CC1 is widely expressed in both nucleus and cytoplasm and plays essential roles in autophagy, cell proliferation and growth, and apoptosis (Nishimura et al., 2011).
By differential display analysis, Chano et al. (2002) identified and cloned RB1CC1 as a gene showing unique expression in a multidrug resistant osteosarcoma cell line. The cDNA encodes a deduced 1,594-amino acid protein containing a consensus nuclear localization signal (KPRK), a leucine zipper motif, and a coiled-coil structure. The protein showed a molecular mass of 180 kD by Western blot analysis. Nuclear localization was confirmed by cell fractionation and immunocytochemistry analysis.
Gan et al. (2005) stated that human FIP200 protein contains 1,591 amino acids.
Maucuer et al. (1995) isolated and cloned an embryonic mouse partial cDNA for Rb1cc1 through a yeast 2-hybrid screen using human stathmin (138120) as bait. Chano et al. (2002) cloned full-length mouse Rb1cc1, which encodes a deduced 1,588-amino acid protein that shares 89% identity with human RB1CC1. Northern blot analysis detected Rb1cc1 transcripts of 6.2 and 6.8 kb that were expressed highly in heart and moderately in kidney, liver, and skeletal muscle. Testis expressed only the 6.2-kb transcript. Western blot and immunohistochemical analyses detected Rb1cc1 in mouse cell nuclei.
Chano et al. (2002) determined that the RB1CC1 gene contains 24 exons and spans 74 kb.
By genomic sequence analysis, Chano et al. (2002) mapped the RB1CC1 gene to chromosome 8q11.2. They mapped the mouse Rb1cc1 gene to a region of chromosome 1A2-A4 that shares homology of synteny with human chromosome 8q11.2.
By Northern blot analysis, Chano et al. (2002) found that expression of RB1CC1 correlated inversely with that of MDR1 (171050). Treatment of sensitive parental osteosarcoma cells with the anticancer agent doxorubicin led to downregulation of RB1CC1 expression and cell death. In contrast, doxorubicin treatment of a derivative cell line expressing MDR1 resulted in maintained and increased RB1CC1 expression as well as cell survival. Semiquantitative RT-PCR showed close correlation between expression of RB1CC1 and expression of the retinoblastoma gene (RB1; 614041) in a panel of cancer cell lines. In addition, exogenous expression of RB1CC1 in 2 leukemia cell lines produced a marked increase in RB1 expression, with no detectable change in MDR1 levels. This induction was found to be due to activation of the RB1 promoter by RB1CC1.
Gan et al. (2005) stated that FIP200 has a role in cell cycle progression. By yeast 2-hybrid analysis of a human heart cDNA library, they found that the N-terminal half of FIP200 bound TSC1 (605284), a protein that heterodimerizes with TSC2 (191092) to form a tumor suppressor complex. Coimmunoprecipitation analysis revealed that FIP200 associated with the TSC1-TSC2 complex in human and mouse cells. Overexpression of FIP200 in 293T cells resulted in increased cell size. Overexpression, deletion, and knockdown studies revealed that this effect was due to disruption of the TSC1-TSC2 complex by FIP200 and relief of TSC1-TSC2-dependent inhibition of S6K (see 608938) phosphorylation. In addition, upregulation of FIP200 alone resulted in S6K phosphorylation and activation. The effect of FIP200 on cell size was independent of its effect in cell cycle progression.
Nishimura et al. (2011) found that transgenic mice overexpressing human RB1CC1 in cartilage developed dwarfism without obvious abnormalities in endochondral ossification or subsequent skeletal development. Overexpression of RB1CC1 in ATDC5 mouse chondrocytes repressed synthesis of type II collagen (see 120140). Reciprocally, Rb1cc1 knockdown in ATDC5 cells enhanced type II collagen synthesis. Analysis of in vitro cell signaling revealed that RB1CC1 repressed type II collagen production via several pathways, including repression of Erk1 (601795)/Erk2 (176948) activity and enhancement of NF-kappa-B (see 164011) signaling.
Somatic Mutations
Chano et al. (2002) found that 7 of 35 (20%) primary breast cancers examined contained mutations in RB1CC1, including 9 large interstitial deletions predicted to yield markedly truncated RB1CC1 proteins. In all 7 cases, the RB1CC1 gene in the germline was wildtype; all deletions represented somatic mutations. Wildtype RB1CC1 and RB1 were absent or significantly less abundant than normal in the 7 cancers with mutations in RB1CC1, but were abundant in cancers without such mutations. In all 7 cancers, both RB1CC1 alleles were inactivated; 2 showed compound heterozygous deletions. Thus, RB1CC1 is frequently mutated in breast cancer and shows characteristics of a classic tumor suppressor gene.
Gan et al. (2006) found that Fip200 +/- mice were normal and fertile, whereas Fip200 -/- embryos were lost at mid/late gestation. Histologic examination of Fip200 -/- embryos revealed severe cardiac abnormalities with generalized edema and disrupted liver architecture with dissecting hemorrhage. In culture, Fip200 -/- mouse embryonic fibroblasts (MEFs) were smaller than normal and showed elevated apoptosis. The reduced size of Fip200 -/- embryos and MEFs was associated with reduced S6k phosphorylation and increased Tsc1/Tsc2 function. Fip200 interacted with the apoptosis signaling molecules Ask1 (MAP3K5; 602448) and Traf2 (601895), and Fip200 -/- cells showed reduced Jnk (MAPK8; 601158) phosphorylation and activation in response to Tnf-alpha (191160) stimulation, leading to Tnf-alpha-induced apoptosis. Gan et al. (2006) concluded that Fip200 functions in 2 important signaling pathways to regulate cell growth and survival.
Liang et al. (2010) targeted Fip200 deletion to neurons in mice. Conditional Fip200 mutant mice were born at the expected mendelian ratio, but about 45% died shortly after birth, and all died by 60 days. Mutant mice were significantly smaller than wildtype and exhibited ataxia around postnatal day 14, which progressed to tremors and stiff movements. Brain size was generally comparable to controls, but cerebellum was reduced in size, with less developed foliation and fissuration. Progressive neuronal loss, spongiosis, and neurite degeneration were detected in mutant cerebellum, and large ubiquitin-positive aggregates were found in Purkinje cells and white matter. No autophagosomes were detected in mutant Purkinje cells, and their mitochondria appeared abnormally condensed. Culture mutant cerebellar neurons were abnormally sensitive to serum withdrawal and were lost via apoptosis. Liang et al. (2010) concluded that Fip200 deletion caused a defect in autophagy, leading to neurodegeneration and spongiosis.
Liu et al. (2010) targeted Fip200 deletion to mouse hematopoietic and endothelial cells. Mutant mice were obtained at less than the expected mendelian ratio, and all died within the first week of birth. Mutant mice showed no hemorrhage or edema, and all vasculature appeared normal. However, they exhibited a significant defect in hematopoiesis, with severe anemia, hematopoietic stem cell (HSC) depletion, increased HSC cycling, and aberrant myeloid expansion. Mutant fetal HSCs had increased mitochondrial mass and reactive oxygen species. Liu et al. (2010) concluded that FIP200 has a potential role in autophagy and maintenance of fetal hematopoiesis and HSCs.
In a tumor sample of primary breast cancer (114480), Chano et al. (2002) found compound heterozygosity for interstitial deletions in the RB1CC1 gene: deletion of exons 3-24 (nucleotides 534-5,322) and 9-23 (nucleotides 1,757-5,187), which would result in frameshifts at codons 4 and 411, respectively. Germline DNA was wildtype.
For discussion of the deletion of exons 9-23 found in the RB1CC1 gene (nucleotides 1,757-5,187) that was found in compound heterozygous state in a tumor sample of primary breast cancer (114480) by Chano et al. (2002), see 606837.0001.
Chano, T., Ikegawa, S., Kontani, K., Okabe, H., Baldini, N., Saeki, Y. Identification of RB1CC1, a novel human gene that can induce RB1 in various human cells. Oncogene 21: 1295-1298, 2002. [PubMed: 11850849] [Full Text: https://doi.org/10.1038/sj.onc.1205178]
Chano, T., Ikegawa, S., Saito-Ohara, F., Inazawa, J., Mabuchi, A., Saeki, Y., Okabe, H. Isolation, characterization and mapping of the mouse and human RB1CC1 genes. Gene 291: 29-34, 2002. [PubMed: 12095676] [Full Text: https://doi.org/10.1016/s0378-1119(02)00585-1]
Chano, T., Kontani, K., Teramoto, K., Okabe, H., Ikegawa, S. Truncating mutations of RB1CC1 in human breast cancers. Nature Genet. 31: 285-288, 2002. [PubMed: 12068296] [Full Text: https://doi.org/10.1038/ng911]
Gan, B., Melkoumian, Z. K., Wu, X., Guan, K.-L., Guan, J.-L. Identification of FIP200 interaction with the TSC1-TSC2 complex and its role in regulation of cell size control. J. Cell Biol. 170: 379-389, 2005. [PubMed: 16043512] [Full Text: https://doi.org/10.1083/jcb.200411106]
Gan, B., Peng, X., Nagy, T., Alcaraz, A., Gu, H., Guan, J.-L. Role of FIP200 in cardiac and liver development and its regulation of TNF-alpha and TSC-mTOR signaling pathways. J. Cell Biol. 175: 121-133, 2006. [PubMed: 17015619] [Full Text: https://doi.org/10.1083/jcb.200604129]
Liang, C.-C., Wang, C., Peng, X., Gan, B., Guan, J.-L. Neural-specific deletion of FIP200 leads to cerebellar degeneration caused by increased neuronal death and axon degeneration. J. Biol. Chem. 285: 3499-3509, 2010. [PubMed: 19940130] [Full Text: https://doi.org/10.1074/jbc.M109.072389]
Liu, F., Lee, J. Y., Wei, H., Tanabe, O., Engel, J. D., Morrison, S. J., Guan, J.-L. FIP200 is required for the cell-autonomous maintenance of fetal hematopoietic stem cells. Blood 116: 4806-4814, 2010. [PubMed: 20716775] [Full Text: https://doi.org/10.1182/blood-2010-06-288589]
Maucuer, A., Camonis, J. H., Sobel, A. Stathmin interaction with a putative kinase and coiled-coil-forming protein domains. Proc. Nat. Acad. Sci. 92: 3100-3104, 1995. [PubMed: 7724523] [Full Text: https://doi.org/10.1073/pnas.92.8.3100]
Nishimura, I., Chano, T., Kita, H., Matsusue, Y., Okabe, H. RB1CC1 protein suppresses type II collagen synthesis in chondrocytes and causes dwarfism. J. Biol. Chem. 286: 43925-43932, 2011. [PubMed: 22049074] [Full Text: https://doi.org/10.1074/jbc.M111.264192]