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. 2011 Jan-Feb;2(1-2):89-98.
doi: 10.18632/oncotarget.221.

Insights into 4E-BP1 and p53 mediated regulation of accelerated cell senescence

Suzan K Chao  1 , Susan Band Horwitz, Hayley M McDaid
Affiliations

Insights into 4E-BP1 and p53 mediated regulation of accelerated cell senescence

Suzan K Chao et al. Oncotarget. 2011 Jan-Feb.

Abstract

Senescence is a valid tumor suppressive mechanism in cancer. Accelerated cell senescence describes the growth arrested state of cells that have been treated with anti-tumor drugs, such as doxorubicin that induce a DNA damage response. Discodermolide, a microtubule-stabilizing agent, is a potent inducer of accelerated cell senescence. Resistance to discodermolide is mediated via resistance to accelerated cell senescence, and is associated with reduced expression of the mTORC1 substrate, 4E-BP1 and increased expression of p53 [1]. Although the association of p53 with senescence induction is well-characterized, senescence reversion in the presence of high expression of p53 has not been well-documented. Furthermore, studies addressing the role of mTOR signaling in regulating senescence have been limited and recent data implicate a novel, senescence-associated role for 4E-BP1 in crosstalk with the transcription factor p53. This research perspective will address these somewhat contradictory findings and summarize recent research regarding senescence and mTORC1 signaling.

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Figures

Figure 1
Figure 1. The p53 senescence pathway
Several triggers such as overexpression of oncogenes, telomere dysfunction or attrition, and genotoxic stress, which includes discodermolide treatment, promote the increased activity of p53. P53 activity and stability is negatively regulated by MDM2 (Murine double minute 2) under normal conditions. Under stress conditions, the DNA damage response is activated and p53 rapidly accumulates to increase the transcription of target genes that will promote either apoptosis or senescence depending on the severity of the damage response.
Figure 2
Figure 2. Discodermolide-induced accelerated cell senescence
Senescence-associated β-galactosidase activity in A549 lung carcinoma cells treated with control (DMSO) or, an IC50 concentration of discodermolide for 6 days.
Figure 3
Figure 3. A simplified schematic of the PI3K/Akt/mTORC1 pathway
Growth factors or hormones can stimulate phosphatidylinositol 3-kinase (PI3K) signaling. Additionally, PTEN is commonly mutated in cancer, causing increased Akt activity and signaling through mTORC1. Activation of PI3K activates Akt, which can phosphorylate TSC2 leading to the inactivation of the TSC1/2 inhibitor complex. Released from inhibition, Rheb can then activate mTORC1. Activated mTORC1 phosphorylates its downstream substrates p70S6k and 4E-BP1. Phosphorylation of p70S6k results in phosphorylation of rpS6. mTORC1 phosphorylation of 4E-BP1 releases 4E-BP1 from eIF4E on the 5' cap of mRNA, and enhances cap-dependent translation. 4E-BP1 inhibits translation of Gas2, which increases the stability of p53 by binding m-calpain and inhibiting its protease activity towards p53. Genotoxic stress activates p53, which induces the transcription and expression of SESNs (SESN1 and SESN2). SESN phosphorylates and forms a complex with AMPK and TSC2 that results in the phosphorylation of TSC2, eventually leading to activation of mTORC1 and its substrates 4E-BP1 and p70S6k.
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References

    1. Chao SK, Lin J, Brouwer-Visser J, Smith AB, 3rd, Horwitz SB, McDaid HM. Resistance to discodermolide, a microtubule-stabilizing agent and senescence inducer, is 4E-BP1-dependent. Proc Natl Acad Sci U S A. 2011;108(1):391–6. - PMC - PubMed
    1. Hayflick L, Moorhead PS. The serial cultivation of human diploid cell strains. Exp Cell Res. 1961;25:585–621. - PubMed
    1. Hayflick L. The Limited in Vitro Lifetime of Human Diploid Cell Strains. Exp Cell Res. 1965;37:614–36. - PubMed
    1. Momand J, Zambetti GP, Olson DC, George D, Levine AJ. The mdm-2 oncogene product forms a complex with the p53 protein and inhibits p53-mediated transactivation. Cell. 1992;69(7):1237–45. - PubMed
    1. Xue W, Zender L, Miething C, Dickins RA, Hernando E, Krizhanovsky V, Cordon-Cardo C, Lowe SW. Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas. Nature. 2007;445(7128):656–60. - PMC - PubMed

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