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CDK4/6 inhibitor-mediated cell overgrowth triggers osmotic and replication stress to promote senescence

Research output: Contribution to journal › Article › peer-review

Standard Standard

CDK4/6 inhibitor-mediated cell overgrowth triggers osmotic and replication stress to promote senescence. / Crozier, Lisa; Foy, Reece; adib, Rozita et al.
In: Molecular Cell, Vol. 83, No. 22, 16.11.2023, p. 4062-4077.

Research output: Contribution to journal › Article › peer-review

HarvardHarvard

Crozier, L, Foy, R, adib, R, Kar, A, Holt, J, Pareri, A, Valverde, J, Riviera, R, Weston, W, Wilson, R, Regnault, C, Whitfield, P, Badonyi, M, Bennett, L, Vernon, E, Gamble, A, Marsh, J, Staples, C, Saurin, A, Barr, A & Ly, T 2023, 'CDK4/6 inhibitor-mediated cell overgrowth triggers osmotic and replication stress to promote senescence', Molecular Cell, vol. 83, no. 22, pp. 4062-4077. https://doi.org/10.1016/j.molcel.2023.10.016

APA

Crozier, L., Foy, R., adib, R., Kar, A., Holt, J., Pareri, A., Valverde, J., Riviera, R., Weston, W., Wilson, R., Regnault, C., Whitfield, P., Badonyi, M., Bennett, L., Vernon, E., Gamble, A., Marsh, J., Staples, C., Saurin, A., ... Ly, T. (2023). CDK4/6 inhibitor-mediated cell overgrowth triggers osmotic and replication stress to promote senescence. Molecular Cell, 83(22), 4062-4077. https://doi.org/10.1016/j.molcel.2023.10.016

CBE

Crozier L, Foy R, adib R, Kar A, Holt J, Pareri A, Valverde J, Riviera R, Weston W, Wilson R, et al. 2023. CDK4/6 inhibitor-mediated cell overgrowth triggers osmotic and replication stress to promote senescence. Molecular Cell. 83(22): 4062-4077. https://doi.org/10.1016/j.molcel.2023.10.016

MLA

Crozier, Lisa et al. "CDK4/6 inhibitor-mediated cell overgrowth triggers osmotic and replication stress to promote senescence". Molecular Cell. 2023, 83(22). 4062-4077. https://doi.org/10.1016/j.molcel.2023.10.016

VancouverVancouver

Crozier L, Foy R, adib R, Kar A, Holt J, Pareri A et al. CDK4/6 inhibitor-mediated cell overgrowth triggers osmotic and replication stress to promote senescence. Molecular Cell. 2023 Nov 16;83(22): 4062-4077. doi: 10.1016/j.molcel.2023.10.016

Author

Crozier, Lisa ; Foy, Reece ; adib, Rozita et al. / CDK4/6 inhibitor-mediated cell overgrowth triggers osmotic and replication stress to promote senescence. In: Molecular Cell. 2023 ; Vol. 83, No. 22. pp. 4062-4077.

RIS

TY - JOUR

T1 - CDK4/6 inhibitor-mediated cell overgrowth triggers osmotic and replication stress to promote senescence

AU - Crozier, Lisa

AU - Foy, Reece

AU - adib, Rozita

AU - Kar, Ananya

AU - Holt, Jordan

AU - Pareri, Aanchal

AU - Valverde, Juan

AU - Riviera, Rene

AU - Weston, William

AU - Wilson, Rona

AU - Regnault, Clement

AU - Whitfield, Phil

AU - Badonyi, Mihaly

AU - Bennett, Laura

AU - Vernon, Ellen

AU - Gamble, Amelia

AU - Marsh, Joseph

AU - Staples, Christopher

AU - Saurin, Adrian

AU - Barr, Alexsis

AU - Ly, Tony

PY - 2023/11/16

Y1 - 2023/11/16

N2 - Abnormal increases in cell size are associated with senescence and cell cycle exit. The mechanisms by which overgrowth primes cells to withdraw from the cell cycle remain unknown. We address this question using CDK4/6 inhibitors, which arrest cells in G0/G1 and are licensed to treat advanced HR+/HER2− breast cancer. We demonstrate that CDK4/6-inhibited cells overgrow during G0/G1, causing p38/p53/p21-dependent cell cycle withdrawal. Cell cycle withdrawal is triggered by biphasic p21 induction. The first p21 wave is caused by osmotic stress, leading to p38- and size-dependent accumulation of p21. CDK4/6 inhibitor washout results in some cells entering S-phase. Overgrown cells experience replication stress, resulting in a second p21 wave that promotes cell cycle withdrawal from G2 or the subsequent G1. We propose that the levels of p21 integrate signals from overgrowth-triggered stresses to determine cell fate. This model explains how hypertrophy can drive senescence and why CDK4/6 inhibitors have long-lasting effects in patients.

AB - Abnormal increases in cell size are associated with senescence and cell cycle exit. The mechanisms by which overgrowth primes cells to withdraw from the cell cycle remain unknown. We address this question using CDK4/6 inhibitors, which arrest cells in G0/G1 and are licensed to treat advanced HR+/HER2− breast cancer. We demonstrate that CDK4/6-inhibited cells overgrow during G0/G1, causing p38/p53/p21-dependent cell cycle withdrawal. Cell cycle withdrawal is triggered by biphasic p21 induction. The first p21 wave is caused by osmotic stress, leading to p38- and size-dependent accumulation of p21. CDK4/6 inhibitor washout results in some cells entering S-phase. Overgrown cells experience replication stress, resulting in a second p21 wave that promotes cell cycle withdrawal from G2 or the subsequent G1. We propose that the levels of p21 integrate signals from overgrowth-triggered stresses to determine cell fate. This model explains how hypertrophy can drive senescence and why CDK4/6 inhibitors have long-lasting effects in patients.

U2 - 10.1016/j.molcel.2023.10.016

DO - 10.1016/j.molcel.2023.10.016

M3 - Article

VL - 83

SP - 4062

EP - 4077

JO - Molecular Cell

JF - Molecular Cell

SN - 1097-2765

IS - 22

ER -