BUB1B
BUB1B（budding uninhibited by benzimidazoles 1 beta）は、ヒトではBUB1B遺伝子にコードされる酵素（プロテインキナーゼ）である[5]。BubR1としても知られ、有糸分裂時に紡錘体チェックポイント（SAC）やキネトコア-微小管相互作用において機能し、染色体の移動と整列を促進するタンパク質として認識されている。BubR1は娘細胞への染色体の適切な分離を保証することで、有糸分裂の正確性を高め、異数性が生じないよう保護している。BubR1は腫瘍形成を防ぐことが提唱されている。
機能
BUB1Bは紡錘体チェックポイント機能や染色体分離に関与するプロテインキナーゼである[6]。このタンパク質はキネトコアに局在し、後期促進複合体（APC/C）を阻害する役割を果たしており、有糸分裂後期の開始を遅らせて適切な染色体分離を保証している。紡錘体チェックポイントの機能不全は多くの種類のがんでみられる[7]。
マウスでは、BubR1の発現上昇によって健康寿命の伸長がみられる[8]。
臨床的意義
BubR1は、がん、老化、多彩異数性モザイク（mosaic variegated aneuploidy、MVA）、心疾患など、さまざまな生物学的過程や病理への関与が示唆されている。BubR1タンパク質レベルは年齢とともに低下することが示されている[8][9][10]。さらに、若年個体でのBubR1の喪失は、老化の加速や加齢関連疾患の早期発症、心機能不全、創傷治癒の遅れ、白内障、脊柱後弯、脂肪喪失や筋消耗（悪液質）、がんなどと関係する[9]。このことはマウスで示されている。
DNA修復
化学放射線療法（CRT）は治癒目的で化学療法と放射線療法を併用する治療法であり、さまざまながんの治療で利用されている。CRTはがん細胞にDNA損傷を誘発することで作用する。膀胱がんの治療前の患者から採取された腫瘍試料と同じ患者のCRT後に再発した試料との比較では、CRT後再発試料ではBUB1Bの発現レベルが増加していることが示されている[11]。こうした発現上昇は代替非相同末端結合（A-NHEJ）と呼ばれる不正確なDNA修復過程を促進すると考えられており、CRTによって引き起こされたDNA損傷が不正確に修復されることでさらなる変異が引き起こされ、腫瘍にCRT抵抗性が誘発されている可能性がある[11]。
相互作用
BUB1Bは次に挙げる因子と相互作用することが示されている。
- AP2B1[12]
- BRCA2[13]
- BUB3[12][14][15]
- CDC20[16][17][18][19][20][21]
- MAD2L1[16]
- CBP[22]
- SIRT2[22][23][24]
- PLK1[25][26][27][28][29]
- PP2A-B56[29][30][31][32]
- HDAC1[33]
- HDAC2/HDAC3[34]
- SNCG[35]
出典
- ^ a b c GRCh38: Ensembl release 89: ENSG00000156970 - Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000040084 - Ensembl, May 2017
- ^ Human PubMed Reference:
- ^ Mouse PubMed Reference:
- ^ “The mouse mitotic checkpoint gene bub1b, a novel bub1 family member, is expressed in a cell cycle-dependent manner”. Genomics 55 (1): 113–117. (January 1999). doi:10.1006/geno.1998.5629. PMID 9889005.
- ^ “CENP-E--dependent BubR1 autophosphorylation enhances chromosome alignment and the mitotic checkpoint”. The Journal of Cell Biology 198 (2): 205–217. (July 2012). doi:10.1083/jcb.201202152. PMC 3410423. PMID 22801780.
- ^ “Entrez Gene: BUB1B BUB1 budding uninhibited by benzimidazoles 1 homolog beta (yeast)”. 2023年6月25日閲覧。
- ^ a b “Increased expression of BubR1 protects against aneuploidy and cancer and extends healthy lifespan”. Nature Cell Biology 15 (1): 96–102. (January 2013). doi:10.1038/ncb2643. PMC 3707109. PMID 23242215.
- ^ a b “BubR1 insufficiency causes early onset of aging-associated phenotypes and infertility in mice”. Nature Genetics 36 (7): 744–749. (July 2004). doi:10.1038/ng1382. PMID 15208629.
- ^ “Physiological relevance of post-translational regulation of the spindle assembly checkpoint protein BubR1”. Cell & Bioscience 11 (1): 76. (April 2021). doi:10.1186/s13578-021-00589-2. PMC 8066494. PMID 33892776.
- ^ a b “Increased BUB1B/BUBR1 expression contributes to aberrant DNA repair activity leading to resistance to DNA-damaging agents”. Oncogene 40 (43): 6210–6222. (October 2021). doi:10.1038/s41388-021-02021-y. PMC 8553621. PMID 34545188.
- ^ a b “The beta2-adaptin clathrin adaptor interacts with the mitotic checkpoint kinase BubR1”. Biochemical and Biophysical Research Communications 298 (5): 720–730. (November 2002). doi:10.1016/S0006-291X(02)02522-6. PMID 12419313.
- ^ “Potential role of BRCA2 in a mitotic checkpoint after phosphorylation by hBUBR1”. Cancer Research 60 (6): 1531–1535. (March 2000). PMID 10749118.
- ^ “A new view of the spindle checkpoint”. The Journal of Cell Biology 154 (5): 909–911. (September 2001). doi:10.1083/jcb.200108010. PMC 2196198. PMID 11535614.
- ^ “The human homologue of Bub3 is required for kinetochore localization of Bub1 and a Mad3/Bub1-related protein kinase”. The Journal of Cell Biology 142 (1): 1–11. (July 1998). doi:10.1083/jcb.142.1.1. PMC 2133037. PMID 9660858.
- ^ a b “Checkpoint inhibition of the APC/C in HeLa cells is mediated by a complex of BUBR1, BUB3, CDC20, and MAD2”. The Journal of Cell Biology 154 (5): 925–936. (September 2001). doi:10.1083/jcb.200102093. PMC 2196190. PMID 11535616.
- ^ “Checkpoint protein BubR1 acts synergistically with Mad2 to inhibit anaphase-promoting complex”. Molecular Biology of the Cell 13 (3): 755–766. (March 2002). doi:10.1091/mbc.01-09-0437. PMC 99596. PMID 11907259.
- ^ “p55CDC/hCDC20 is associated with BUBR1 and may be a downstream target of the spindle checkpoint kinase”. Oncogene 19 (40): 4557–4562. (September 2000). doi:10.1038/sj.onc.1203803. PMID 11030144.
- ^ “Rapid microtubule-independent dynamics of Cdc20 at kinetochores and centrosomes in mammalian cells”. The Journal of Cell Biology 158 (5): 841–847. (September 2002). doi:10.1083/jcb.200201135. PMC 2173153. PMID 12196507.
- ^ “Mammalian mad2 and bub1/bubR1 recognize distinct spindle-attachment and kinetochore-tension checkpoints”. Proceedings of the National Academy of Sciences of the United States of America 98 (8): 4492–4497. (April 2001). Bibcode: 2001PNAS...98.4492S. doi:10.1073/pnas.081076898. PMC 31862. PMID 11274370.
- ^ “The APC/C maintains the spindle assembly checkpoint by targeting Cdc20 for destruction”. Nature Cell Biology 10 (12): 1411–1420. (December 2008). doi:10.1038/ncb1799. PMC 2635557. PMID 18997788.
- ^ a b “SIRT2 induces the checkpoint kinase BubR1 to increase lifespan”. The EMBO Journal 33 (13): 1438–1453. (July 2014). doi:10.15252/embj.201386907. PMC 4194088. PMID 24825348.
- ^ “Deacetylation of the mitotic checkpoint protein BubR1 at lysine 250 by SIRT2 and subsequent effects on BubR1 degradation during the prometaphase/anaphase transition”. Biochemical and Biophysical Research Communications 453 (3): 588–594. (October 2014). doi:10.1016/j.bbrc.2014.09.128. PMID 25285631.
- ^ “Sirt2-BubR1 acetylation pathway mediates the effects of advanced maternal age on oocyte quality”. Aging Cell 17 (1): e12698. (February 2018). doi:10.1111/acel.12698. PMC 5770883. PMID 29067790.
- ^ “Phosphorylation sites in BubR1 that regulate kinetochore attachment, tension, and mitotic exit”. The Journal of Cell Biology 183 (4): 667–680. (November 2008). doi:10.1083/jcb.200805163. PMC 2582891. PMID 19015317.
- ^ “Polo-like kinase 1 facilitates chromosome alignment during prometaphase through BubR1” (English). The Journal of Biological Chemistry 282 (20): 15217–15227. (May 2007). doi:10.1074/jbc.M611053200. PMID 17376779.
- ^ “Tension-sensitive Plk1 phosphorylation on BubR1 regulates the stability of kinetochore microtubule interactions”. Genes & Development 21 (17): 2205–2219. (September 2007). doi:10.1101/gad.436007. PMC 1950859. PMID 17785528.
- ^ “BubR1 localizes to centrosomes and suppresses centrosome amplification via regulating Plk1 activity in interphase cells”. Oncogene 28 (31): 2806–2820. (August 2009). doi:10.1038/onc.2009.141. PMID 19503101.
- ^ a b “Integration of kinase and phosphatase activities by BUBR1 ensures formation of stable kinetochore-microtubule attachments” (English). Developmental Cell 23 (4): 745–755. (October 2012). doi:10.1016/j.devcel.2012.09.005. PMID 23079597.
- ^ “Direct binding between BubR1 and B56-PP2A phosphatase complexes regulate mitotic progression”. Journal of Cell Science 126 (Pt 5): 1086–1092. (March 2013). doi:10.1242/jcs.122481. PMID 23345399.
- ^ “BUBR1 Pseudokinase Domain Promotes Kinetochore PP2A-B56 Recruitment, Spindle Checkpoint Silencing, and Chromosome Alignment” (English). Cell Reports 33 (7): 108397. (November 2020). doi:10.1016/j.celrep.2020.108397. PMID 33207204.
- ^ “Crystal structure of a PP2A B56-BubR1 complex and its implications for PP2A substrate recruitment and localization”. Protein & Cell 7 (7): 516–526. (July 2016). doi:10.1007/s13238-016-0283-4. PMC 4930772. PMID 27350047.
- ^ “WD repeat-containing mitotic checkpoint proteins act as transcriptional repressors during interphase”. FEBS Letters 575 (1–3): 23–29. (September 2004). doi:10.1016/j.febslet.2004.07.089. PMID 15388328.
- ^ “HDAC2/3 binding and deacetylation of BubR1 initiates spindle assembly checkpoint silencing”. The FEBS Journal 284 (23): 4035–4050. (December 2017). doi:10.1111/febs.14286. PMID 28985013.
- ^ “Breast cancer-specific gene 1 interacts with the mitotic checkpoint kinase BubR1”. Oncogene 22 (48): 7593–7599. (October 2003). doi:10.1038/sj.onc.1206880. PMID 14576821.
関連文献
- “Activation of the yeast SSK2 MAP kinase kinase kinase by the SSK1 two-component response regulator”. The EMBO Journal 17 (5): 1385–1394. (March 1998). doi:10.1093/emboj/17.5.1385. PMC 1170486. PMID 9482735.
- “Mutations of mitotic checkpoint genes in human cancers”. Nature 392 (6673): 300–303. (March 1998). Bibcode: 1998Natur.392..300C. doi:10.1038/32688. PMID 9521327.
- “Identification of a novel gene--SSK1--in human endothelial cells exposed to shear stress”. Biochemical and Biophysical Research Communications 246 (3): 881–887. (May 1998). doi:10.1006/bbrc.1998.8713. PMID 9618306.
- “Characterization of the kinetochore binding domain of CENP-E reveals interactions with the kinetochore proteins CENP-F and hBUBR1”. The Journal of Cell Biology 143 (1): 49–63. (October 1998). doi:10.1083/jcb.143.1.49. PMC 2132809. PMID 9763420.
- “The hBUB1 and hBUBR1 kinases sequentially assemble onto kinetochores during prophase with hBUBR1 concentrating at the kinetochore plates in mitosis”. Chromosoma 107 (6–7): 386–396. (December 1998). doi:10.1007/s004120050322. PMID 9914370.
- “Characterization of MAD2B and other mitotic spindle checkpoint genes”. Genomics 58 (2): 181–187. (June 1999). doi:10.1006/geno.1999.5831. PMID 10366450.
- “Human BUBR1 is a mitotic checkpoint kinase that monitors CENP-E functions at kinetochores and binds the cyclosome/APC”. The Journal of Cell Biology 146 (5): 941–954. (September 1999). doi:10.1083/jcb.146.5.941. PMC 2169490. PMID 10477750.
- “BUBR1 phosphorylation is regulated during mitotic checkpoint activation”. Cell Growth & Differentiation 10 (11): 769–775. (November 1999). PMID 10593653.
- “Components of the human spindle checkpoint control mechanism localize specifically to the active centromere on dicentric chromosomes”. Human Genetics 107 (4): 376–384. (October 2000). doi:10.1007/s004390000386. PMID 11129339.
- “Systematic subcellular localization of novel proteins identified by large-scale cDNA sequencing”. EMBO Reports 1 (3): 287–292. (September 2000). doi:10.1093/embo-reports/kvd058. PMC 1083732. PMID 11256614.
- “A role for the Adenomatous Polyposis Coli protein in chromosome segregation”. Nature Cell Biology 3 (4): 429–432. (April 2001). doi:10.1038/35070123. PMID 11283619.
- “Mad2-Independent inhibition of APCCdc20 by the mitotic checkpoint protein BubR1”. Developmental Cell 1 (2): 227–237. (August 2001). doi:10.1016/S1534-5807(01)00019-3. PMID 11702782.
- “Genetic and epigenetic inactivation of mitotic checkpoint genes hBUB1 and hBUBR1 and their relationship to survival”. Cancer Research 62 (1): 13–17. (January 2002). PMID 11782350.
- “Kinetochore localisation and phosphorylation of the mitotic checkpoint components Bub1 and BubR1 are differentially regulated by spindle events in human cells”. Journal of Cell Science 114 (Pt 24): 4385–4395. (December 2001). doi:10.1242/jcs.114.24.4385. PMID 11792804.
外部リンク
- Human BUB1B genome location and BUB1B gene details page in the UCSC Genome Browser.