Transient activation of p53 in G2 phase is sufficient to induce senescence

Lenno Krenning; Femke M. Feringa; Indra A. Shaltiel; Jeroen vandenBerg; René H. Medema

doi:10.1016/j.molcel.2014.05.007

Transient activation of p53 in G2 phase is sufficient to induce senescence

Lenno Krenning
, Femke M. Feringa
, Indra A. Shaltiel
, Jeroen vandenBerg
, René H. Medema^*

^*Corresponding author for this work

Research output: Contribution to Journal › Article › Academic › peer-review

Abstract

DNA damage can result in a transient cell-cycle arrest or lead to permanent cell-cycle withdrawal. Here we show that the decision to irreversibly withdraw from the cell cycle is made within a few hours following damage in G2 cells. This permanent arrest is dependent on induction of p53 and p21, resulting in the nuclear retention of Cyclin B1. This rapid response is followed by the activation of the APC/C^Cdh1 (the anaphase-promoting complex/cyclosome and its coactivator Cdh1) several hours later. Inhibition of APC/C^Cdh1 activity fails to prevent cell-cycle withdrawal, whereas preventing nuclear retention of Cyclin B1 does allow cells to remain in cycle. Importantly, transient induction of p53 in G2 cells is sufficient to induce senescence. Taken together, these results indicate that a rapid and transient pulse of p53 in G2 can drive nuclear retention of Cyclin B1 as the first irreversible step in the onset of senescence.

Original language	English
Pages (from-to)	59-72
Number of pages	14
Journal	Molecular Cell
Volume	55
Issue number	1
DOIs	https://doi.org/10.1016/j.molcel.2014.05.007
Publication status	Published - 3 Jul 2014
Externally published	Yes

Funding

We thank members of the Medema lab for helpful discussions and the flow cytometry and digital microscopy facilities for technical support. This work was supported by research grants from the NWO Graduate Program (022.001.003), the NWO Gravitation Program (Cancer Genomics Center, CGC.nl), and the Dutch Cancer Society (KWF) (NKI 2009-4478).

Access to Document

10.1016/j.molcel.2014.05.007

Persistent URL (handle)

Persistent link

Cite this

@article{40e7946c2116469fa442f384031a617b,

title = "Transient activation of p53 in G2 phase is sufficient to induce senescence",

abstract = "DNA damage can result in a transient cell-cycle arrest or lead to permanent cell-cycle withdrawal. Here we show that the decision to irreversibly withdraw from the cell cycle is made within a few hours following damage in G2 cells. This permanent arrest is dependent on induction of p53 and p21, resulting in the nuclear retention of Cyclin B1. This rapid response is followed by the activation of the APC/CCdh1 (the anaphase-promoting complex/cyclosome and its coactivator Cdh1) several hours later. Inhibition of APC/CCdh1 activity fails to prevent cell-cycle withdrawal, whereas preventing nuclear retention of Cyclin B1 does allow cells to remain in cycle. Importantly, transient induction of p53 in G2 cells is sufficient to induce senescence. Taken together, these results indicate that a rapid and transient pulse of p53 in G2 can drive nuclear retention of Cyclin B1 as the first irreversible step in the onset of senescence.",

author = "Lenno Krenning and Feringa, \{Femke M.\} and Shaltiel, \{Indra A.\} and Jeroen vandenBerg and Medema, \{Ren{\'e} H.\}",

year = "2014",

month = jul,

day = "3",

doi = "10.1016/j.molcel.2014.05.007",

language = "English",

volume = "55",

pages = "59--72",

journal = "Molecular Cell",

issn = "1097-2765",

publisher = "Cell Press",

number = "1",

}

TY - JOUR

T1 - Transient activation of p53 in G2 phase is sufficient to induce senescence

AU - Krenning, Lenno

AU - Feringa, Femke M.

AU - Shaltiel, Indra A.

AU - vandenBerg, Jeroen

AU - Medema, René H.

PY - 2014/7/3

Y1 - 2014/7/3

N2 - DNA damage can result in a transient cell-cycle arrest or lead to permanent cell-cycle withdrawal. Here we show that the decision to irreversibly withdraw from the cell cycle is made within a few hours following damage in G2 cells. This permanent arrest is dependent on induction of p53 and p21, resulting in the nuclear retention of Cyclin B1. This rapid response is followed by the activation of the APC/CCdh1 (the anaphase-promoting complex/cyclosome and its coactivator Cdh1) several hours later. Inhibition of APC/CCdh1 activity fails to prevent cell-cycle withdrawal, whereas preventing nuclear retention of Cyclin B1 does allow cells to remain in cycle. Importantly, transient induction of p53 in G2 cells is sufficient to induce senescence. Taken together, these results indicate that a rapid and transient pulse of p53 in G2 can drive nuclear retention of Cyclin B1 as the first irreversible step in the onset of senescence.

AB - DNA damage can result in a transient cell-cycle arrest or lead to permanent cell-cycle withdrawal. Here we show that the decision to irreversibly withdraw from the cell cycle is made within a few hours following damage in G2 cells. This permanent arrest is dependent on induction of p53 and p21, resulting in the nuclear retention of Cyclin B1. This rapid response is followed by the activation of the APC/CCdh1 (the anaphase-promoting complex/cyclosome and its coactivator Cdh1) several hours later. Inhibition of APC/CCdh1 activity fails to prevent cell-cycle withdrawal, whereas preventing nuclear retention of Cyclin B1 does allow cells to remain in cycle. Importantly, transient induction of p53 in G2 cells is sufficient to induce senescence. Taken together, these results indicate that a rapid and transient pulse of p53 in G2 can drive nuclear retention of Cyclin B1 as the first irreversible step in the onset of senescence.

UR - https://www.scopus.com/pages/publications/84903715003

UR - https://www.scopus.com/pages/publications/84903715003#tab=citedBy

U2 - 10.1016/j.molcel.2014.05.007

DO - 10.1016/j.molcel.2014.05.007

M3 - Article

C2 - 24910099

AN - SCOPUS:84903715003

SN - 1097-2765

VL - 55

SP - 59

EP - 72

JO - Molecular Cell

JF - Molecular Cell

IS - 1

ER -

Transient activation of p53 in G2 phase is sufficient to induce senescence

Abstract

Funding

Access to Document

Persistent URL (handle)

Other files and links

Fingerprint

Cite this