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Commentary: locating the restriction point.

Brooks, RF (2023) Commentary: locating the restriction point. Cell Div, 18 (1). p. 2. ISSN 1747-1028 https://doi.org/10.1186/s13008-023-00085-8
SGUL Authors: Brooks, Robert Frederick

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Abstract

Attempts to map the Restriction Point in the mammalian cell cycle typically involve stimulating quiescent cells with mitogens for increasing intervals, removing the stimulus and then determining the proportion of cells that reach S phase at some point later. This "fixed point" estimate assumes that further cell cycle commitment ceases as soon as the stimulus is removed. In fact, kinetic analysis shows that the probability of cell cycle commitment does not fall back to its initial low value, immediately after a pulse of mitogens, but may instead remain slightly elevated for some while afterwards, compared to the starting quiescent population. Thus, cells entering S phase after a brief exposure to mitogens are not those that pass the Restriction Point early. Rather, they represent cells that continue on to S phase as a result of this residual, low probability of cell cycle commitment. Instead, the mitogen-regulated process(es) affecting the probability of cell cycle commitment are much closer to the start of S phase itself. Since the acquisition of (apparent) mitogen independence is such a poor indicator of the timing of cell cycle commitment, it is argued that a better measure is the point of insensitivity to CDK4,6 inhibitors such as palbociclib, which indicates when hyperphosphorylation of the Retinoblastoma Protein, RB, ceases to be dependent on mitogen-signalling pathways regulating CDK4,6/cyclin D activity.

Item Type: Article
Additional Information: © The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
Keywords: Cell cycle commitment, Cyclin D, Cyclin E, Cyclin-dependent kinase 2 (CDK2), Cyclin-dependent kinases 4 and 6 (CDK4,6), Mitogen stimulation, Palbociclib, Quiescence, Restriction point, Retinoblastoma protein (RB), 1199 Other Medical and Health Sciences, Developmental Biology
SGUL Research Institute / Research Centre: Academic Structure > Molecular and Clinical Sciences Research Institute (MCS)
Journal or Publication Title: Cell Div
ISSN: 1747-1028
Language: eng
Dates:
DateEvent
10 February 2023Published
12 January 2023Accepted
Publisher License: Creative Commons: Attribution 4.0
PubMed ID: 36765359
Go to PubMed abstract
URI: https://openaccess.sgul.ac.uk/id/eprint/115180
Publisher's version: https://doi.org/10.1186/s13008-023-00085-8

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