The DOI matches its Crossref record; 11 of the 11 references it cites were found in a registry or an index.
Stimulus‐dependent dynamics of p53 in single cells
Open accessAbstract
Many biological networks respond to various inputs through a common signaling molecule that triggers distinct cellular outcomes. One potential mechanism for achieving specific input-output relationships is to trigger distinct dynamical patterns in response to different stimuli. Here we focused on the dynamics of p53, a tumor suppressor activated in response to cellular stress. We quantified the dynamics of p53 in individual cells in response to UV and observed a single pulse that increases in amplitude and duration in proportion to the UV dose. This graded response contrasts with the previously described series of fixed pulses in response to γ-radiation. We further found that while γ-triggered p53 pulses are excitable, the p53 response to UV is not excitable and depends on continuous signaling from the input-sensing kinases. Using mathematical modeling and experiments, we identified feedback loops that contribute to specific features of the stimulus-dependent dynamics of p53, including excitability and input-duration dependency. Our study shows that different stresses elicit different temporal profiles of p53, suggesting that modulation of p53 dynamics might be used to achieve specificity in this network.
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Citations
Cites
Mdm2 promotes the rapid degradation of p53
Haupt, Y., Maya, R., Kazaz, A., & Oren, M. (1997) · Nature · doi:10.1038/387296a0 · Cited by 4,506
Regulation of p53 stability by Mdm2
Kubbutat, M. H. G., Jones, S. N., & Vousden, K. H. (1997) · Nature · doi:10.1038/387299a0 · Cited by 3,312 · cited 1×
“…DSBs (γ, NCS) ATM Mdm2 P Ser-395 Inhibition + Rapid degradation ssDNA (UV) ATR Mdm2 P Ser-407 Inhibition 10 Gy γ 4 Molecular Systems Biology 2011 & 2011 EMBO and Macmillan Publishers Limited targets p53 for degradation (Barak et al, 1993; Wu et al, 1993; Haupt et al, 1997; Kubbutat et al, 1997).”
BackgroundThe p53 pathway: positive and negative feedback loops
Harris, S. L., & Levine, A. J. (2005) · Oncogene · doi:10.1038/sj.onc.1208615 · Cited by 1,967
ATR: an essential regulator of genome integrity
Cimprich, K. A., & Cortez, D. (2008) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2450 · Cited by 1,798
Post-translational modification of p53 in tumorigenesis
Bode, A. M., & Dong, Z. (2004) · Nature Reviews Cancer · doi:10.1038/nrc1455 · Cited by 1,270
ATM- and cell cycle-dependent regulation of ATR in response to DNA double-strand breaks
Jazayeri, A., Falck, J., Lukas, C., Bartek, J., Smith, G. C. M., Lukas, J., & Jackson, S. P. (2006) · Nature Cell Biology · doi:10.1038/ncb1337 · Cited by 1,064
ATM-dependent phosphorylation of Mdm2 on serine 395: role in p53 activation by DNA damage
Maya, R., Balass, M., Kim, S.-T., Shkedy, D., Leal, J.-F. M., Shifman, O., Moas, M., Buschmann, T., Ronai, Z., Shiloh, Y., et al. (2001) · Genes & Development · doi:10.1101/gad.886901 · Cited by 731 · cited 1×
“Error bars represent s.e.m. & 2011 EMBO and Macmillan Publishers Limited Molecular Systems Biology 2011 5 Mdm2 is phosphorylated by ATM on Ser-395 (Khosravi et al, 1999; Maya et al, 2001; Michael and Oren, 2003).”
BackgroundCoping with stress: multiple ways to activate p53
Horn, H. F., & Vousden, K. H. (2007) · Oncogene · doi:10.1038/sj.onc.1210263 · Cited by 522 · cited 1×
“The tumor suppressor protein p53 is induced in response to many stress signals (Horn and Vousden, 2007) and activates various stress-response programs including cell-cycle arrest, senescence, and apoptosis.”
BackgroundPPM1D dephosphorylates Chk1 and p53 and abrogates cell cycle checkpoints
Lu, X., Nannenga, B., & Donehower, L. A. (2005) · Genes & Development · doi:10.1101/gad.1291305 · Cited by 389
Accelerated MDM2 auto‐degradation induced by DNA‐damage kinases is required for p53 activation
Stommel, J. M., & Wahl, G. M. (2004) · The EMBO Journal · doi:10.1038/sj.emboj.7600145 · Cited by 386 · cited 2×
“This phosphorylation destabilizes Mdm2 by increasing its autoubiquitination and subsequent proteasomal degradation (Stommel and Wahl, 2004) (Figure 3E).”
BackgroundFunctional role of Mdm2 phosphorylation by ATR in attenuation of p53 nuclear export
Shinozaki, T., Nota, A., Taya, Y., & Okamoto, K. (2003) · Oncogene · doi:10.1038/sj.onc.1207176 · Cited by 93
Cited by
p53 Dynamics Control Cell Fate
Purvis, J. E., Karhohs, K. W., Mock, C., Batchelor, E., Loewer, A., & Lahav, G. (2012) · Science · doi:10.1126/science.1218351 · Cited by 770
Self-citationFunctional Roles of Pulsing in Genetic Circuits
Levine, J. H., Lin, Y., & Elowitz, M. B. (2013) · Science · doi:10.1126/science.1239999 · Cited by 377
Dynamic Ligand Discrimination in the Notch Signaling Pathway
Nandagopal, N., Santat, L. A., LeBon, L., Sprinzak, D., Bronner, M. E., & Elowitz, M. B. (2018) · Cell · doi:10.1016/j.cell.2018.01.002 · Cited by 322
Cell-to-cell variation in p53 dynamics leads to fractional killing.
Paek, A. L., Liu, J. C., Loewer, A., Forrester, W. C., & Lahav, G. (2016) · Cell · doi:10.1016/j.cell.2016.03.025 · Cited by 292
Self-citationTransient Activation of p53 in G2 Phase Is Sufficient to Induce Senescence
Krenning, L., Feringa, F. M., Shaltiel, I. A., van den Berg, J., & Medema, R. H. (2014) · Molecular Cell · doi:10.1016/j.molcel.2014.05.007 · Cited by 193
Metadata
- Authors
- Batchelor, E., Loewer, A., Mock, C., & Lahav, G.
- Venue
- Molecular Systems Biology
- Published
- 2011-01
- Volume
- 7
- Issue
- 1
- Pages
- 488-488
- ISSN
- 1744-4292 (ISSN-L)
- OpenAlex
- W2167921512
- Cited by
- 322
- References
- 11
- FWCI
- 7.99
- Type
- journal article
- Language
- en
- Open access
- gold
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