Basal Dynamics of p53 Reveal Transcriptionally Attenuated Pulses in Cycling Cells

Alexander Loewer, Eric Batchelor, Giorgio Gaglia, Galit Lahav

Research output: Contribution to journalArticlepeer-review

174 Scopus citations

Abstract

The tumor suppressor p53 is activated by stress and leads to cellular outcomes such as apoptosis and cell-cycle arrest. Its activation must be highly sensitive to ensure that cells react appropriately to damage. However, proliferating cells often encounter transient damage during normal growth, where cell-cycle arrest or apoptosis may be unfavorable. How does the p53 pathway achieve the right balance between high sensitivity and tolerance to intrinsic damage? Using quantitative time-lapse microscopy of individual human cells, we found that proliferating cells show spontaneous pulses of p53, which are triggered by an excitable mechanism during cell-cycle phases associated with intrinsic DNA damage. However, in the absence of sustained damage, posttranslational modifications keep p53 inactive, preventing it from inducing p21 expression and cell-cycle arrest. Our approach of quantifying basal dynamics in individual cells can now be used to study how other pathways in human cells achieve sensitivity in noisy environments.

Original languageEnglish (US)
Pages (from-to)89-100
Number of pages12
JournalCell
Volume142
Issue number1
DOIs
StatePublished - Jul 2010
Externally publishedYes

Bibliographical note

Funding Information:
We thank G. Hornung and M. Oren for the p21 reporter construct; T. Mitchison for the Lamin A/C antibody and for comments; K. Janes and J. Brugge for MCF10A; B. Vogelstein for HCT p53 −/− ; S. Elledge for RPE-hTERT and R. Agami for MCF7+p53shRNA cell lines; O. Gozani and E. Appella for antibodies; Martin Tenniswood for help with obtaining JW1521; J. Alzate and M. DiBona for technical assistance; J. Waters (Nikon Imaging Center at Harvard Medical School) for advice on live-cell imaging; and J. Paulsson, U. Alon, Y. Pilpel, M. Springer, B. Ward, M. Jain, and S. Loewer for comments and discussions. This research was supported by National Institutes of Health grant GM083303. A.L. was supported by fellowships from the German Research Foundation and the Charles A. King Trust. E.B. was supported by the American Cancer Society, P. and E. Taft Postdoctoral Fellowship.

Keywords

  • Cellcycle
  • Sysbio

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