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  Tissue-Specific Chk1 Activation Determines Apoptosis by Regulating the Balance of p53 and p21

van Jaarsveld, M., Deng, D., Wiemer, E. A. C., & Zi, Z. (2019). Tissue-Specific Chk1 Activation Determines Apoptosis by Regulating the Balance of p53 and p21. iScience, 12, 27-40. doi:10.1016/j.isci.2019.01.001.

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Item Permalink: http://hdl.handle.net/21.11116/0000-0003-6684-5 Version Permalink: http://hdl.handle.net/21.11116/0000-0003-6685-4
Genre: Journal Article

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van Jaarsveld.pdf (Publisher version), 7MB
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© 2019 The Author(s)

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 Creators:
van Jaarsveld, Marijn1, Author              
Deng, Difan1, Author              
Wiemer, Erik A. C. , Author
Zi, Zhike1, Author              
Affiliations:
1Cell Signaling Dynamics (Zhike Zi), Independent Junior Research Groups (OWL), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_2117284              

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Free keywords: Bioinformatics; Cancer Systems Biology; Mathematical Biosciences; Systems Biology
 Abstract: The DNA damage response (DDR) protects cells against genomic instability. Surprisingly, little is known about the differences in DDR across tissues, which may affect cancer evolutionary trajectories and chemotherapy response. Using mathematical modeling and quantitative experiments, we found that the DDR is regulated differently in human breast and lung primary cells. Equal levels of cisplatin-DNA lesions caused stronger Chk1 activation in lung cells, leading to resistance. In contrast, breast cells were more resistant and showed more Chk2 activation in response to doxorubicin. Further analyses indicate that Chk1 activity played a regulatory role in p53 phosphorylation, whereas Chk2 activity was essential for p53 activation and p21 expression. We propose a novel "friction model," in which the balance of p53 and p21 levels contributes to the apoptotic response in different tissues. Our results suggest that modulating the balance of p53 and p21 dynamics could optimize the response to chemotherapy.

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Language(s): eng - English
 Dates: 2018-12-312019-02-22
 Publication Status: Published online
 Pages: -
 Publishing info: -
 Table of Contents: -
 Rev. Method: -
 Identifiers: DOI: 10.1016/j.isci.2019.01.001
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Title: iScience
Source Genre: Journal
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Publ. Info: Cell Press
Pages: - Volume / Issue: 12 Sequence Number: - Start / End Page: 27 - 40 Identifier: ISSN: 2589-0042