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Aurora B表达增加会降低底物磷酸化并诱导染色体不稳定。

Increased Aurora B expression reduces substrate phosphorylation and induces chromosomal instability.

作者信息

Britigan Eric M C, Wan Jun, Sam Daniel K, Copeland Sarah E, Lasek Amber L, Hrycyniak Laura C F, Wang Lei, Audhya Anjon, Burkard Mark E, Roopra Avtar, Weaver Beth A

机构信息

Molecular and Cellular Pharmacology Graduate Training Program, University of Wisconsin-Madison, Madison, WI, United States.

Physiology Graduate Training Program, University of Wisconsin-Madison, Madison, WI, United States.

出版信息

Front Cell Dev Biol. 2022 Oct 13;10:1018161. doi: 10.3389/fcell.2022.1018161. eCollection 2022.

DOI:10.3389/fcell.2022.1018161
PMID:36313574
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9606593/
Abstract

Increased Aurora B protein expression, which is common in cancers, is expected to increase Aurora B kinase activity, yielding elevated phosphorylation of Aurora B substrates. In contrast, here we show that elevated expression of Aurora B reduces phosphorylation of six different Aurora B substrates across three species and causes defects consistent with Aurora B inhibition. Complexes of Aurora B and its binding partner INCENP autophosphorylate in trans to achieve full Aurora B activation. Increased expression of Aurora B mislocalizes INCENP, reducing the local concentration of Aurora B:INCENP complexes at the inner centromere/kinetochore. Co-expression of INCENP rescues Aurora B kinase activity and mitotic defects caused by elevated Aurora B. However, INCENP expression is not elevated in concert with Aurora B in breast cancer, and increased expression of Aurora B causes resistance rather than hypersensitivity to Aurora B inhibitors. Thus, increased Aurora B expression reduces, rather than increases, Aurora B kinase activity.

摘要

Aurora B蛋白表达增加在癌症中很常见，预计会增加Aurora B激酶活性，导致Aurora B底物的磷酸化水平升高。相比之下，我们在此表明，Aurora B表达升高会降低三个物种中六种不同Aurora B底物的磷酸化水平，并导致与Aurora B抑制一致的缺陷。Aurora B及其结合伴侣INCENP的复合物通过反式自磷酸化来实现Aurora B的完全激活。Aurora B表达增加会使INCENP定位错误，降低着丝粒内/动粒处Aurora B:INCENP复合物的局部浓度。共表达INCENP可挽救由Aurora B升高引起的Aurora B激酶活性和有丝分裂缺陷。然而，在乳腺癌中，INCENP的表达并未与Aurora B协同升高，Aurora B表达增加会导致对Aurora B抑制剂产生抗性而非超敏反应。因此，Aurora B表达增加会降低而非增加Aurora B激酶活性。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3f1d/9606593/5dbdffa00fe3/fcell-10-1018161-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3f1d/9606593/1866dfd491e0/fcell-10-1018161-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3f1d/9606593/d3fbceb30b62/fcell-10-1018161-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3f1d/9606593/1834cea56f34/fcell-10-1018161-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3f1d/9606593/f56f0566af26/fcell-10-1018161-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3f1d/9606593/5b96a7bc806d/fcell-10-1018161-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3f1d/9606593/c578bf32e4e4/fcell-10-1018161-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3f1d/9606593/5dbdffa00fe3/fcell-10-1018161-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3f1d/9606593/1866dfd491e0/fcell-10-1018161-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3f1d/9606593/d3fbceb30b62/fcell-10-1018161-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3f1d/9606593/1834cea56f34/fcell-10-1018161-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3f1d/9606593/f56f0566af26/fcell-10-1018161-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3f1d/9606593/5b96a7bc806d/fcell-10-1018161-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3f1d/9606593/c578bf32e4e4/fcell-10-1018161-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3f1d/9606593/5dbdffa00fe3/fcell-10-1018161-g007.jpg

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Mol Biol Cell. 2022 Aug 1;33(9):ar85. doi: 10.1091/mbc.E21-11-0590. Epub 2022 Jun 15.
2
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Hum Cell. 2022 Mar;35(2):678-693. doi: 10.1007/s13577-022-00675-8. Epub 2022 Jan 28.
3
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Tumour Virus Res. 2025 Feb 7;19:200314. doi: 10.1016/j.tvr.2025.200314.
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Optimal strategies for correcting merotelic chromosome attachments in anaphase.纠正后期染色体错连的最佳策略。
Proc Natl Acad Sci U S A. 2025 Feb 4;122(5):e2416459122. doi: 10.1073/pnas.2416459122. Epub 2025 Jan 30.
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