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TP53 and MTOR crosstalk to regulate cellular senescence.

Galluzzi L, Kepp O, Kroemer G - Aging (Albany NY) (2010)

Bottom Line: The full spectrum of activities of the tumor suppressor p53 (TP53) has not been completely elucidated yet.Recently, it was demonstrated that TP53 communicates with the metabolic regulator mechanistic target of rapamycin (MTOR) to determine whether stressed cells undergo cell death, reversible quiescence or irreversible senescence, thereby adding yet another level of complexity to the signaling network that emanate from TP53.

View Article: PubMed Central - PubMed

ABSTRACT
The full spectrum of activities of the tumor suppressor p53 (TP53) has not been completely elucidated yet. Recently, it was demonstrated that TP53 communicates with the metabolic regulator mechanistic target of rapamycin (MTOR) to determine whether stressed cells undergo cell death, reversible quiescence or irreversible senescence, thereby adding yet another level of complexity to the signaling network that emanate from TP53.

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Related in: MedlinePlus

TP53 levels determine whether CDKN1A will orchestrate irreversible senescence or quiescence.(A) Low doses of doxorubicin are sufficient to trigger TP53-mediated transactivation of the cell cycle-arresting protein CDKN1A. Under conditions in which the MTOR pathway is active, prolonged cell cycle arrest results in irreversible senescence. (B) High doxorubicin concentrations (or nutlin-3a alone or in combination with low doses of doxorubicin) not only drive TP53-mediated CDKN1A transactivation but might also result in the induction of one (or more) senescence-suppressing factors. In this scenario, MTOR activity is suppressed and CDKN1A-mediated cell cycle arrest is reversible (quiescence). By pharmacologically inhibiting MTOR, rapamycin also exerts senescence-suppressing functions.
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Figure 1: TP53 levels determine whether CDKN1A will orchestrate irreversible senescence or quiescence.(A) Low doses of doxorubicin are sufficient to trigger TP53-mediated transactivation of the cell cycle-arresting protein CDKN1A. Under conditions in which the MTOR pathway is active, prolonged cell cycle arrest results in irreversible senescence. (B) High doxorubicin concentrations (or nutlin-3a alone or in combination with low doses of doxorubicin) not only drive TP53-mediated CDKN1A transactivation but might also result in the induction of one (or more) senescence-suppressing factors. In this scenario, MTOR activity is suppressed and CDKN1A-mediated cell cycle arrest is reversible (quiescence). By pharmacologically inhibiting MTOR, rapamycin also exerts senescence-suppressing functions.

Mentions: Based on the fascinating results obtained by Leontieva et al. [8], it can be speculated that nuclear TP53 might simultaneously transactivate the cell cycle-arresting factor CDKN1A and one or more hitherto unidentified anti-senescence (and perhaps pro-autophagic?) protein(s) that would operate similar to rapamycin, through the inhibition of MTOR. How would then the senescence-inducing activity of TP53 prevail over TP53-mediated senescence suppression (and vice versa)? As a possibility, the promoter of CDKN1Amight display a high affinity for TP53, while the promoter of the TP53 target that suppresses MTOR activity might require high TP53 concentrations for efficient transactivation. This hypothesis takes into consideration the fact that CDKN1A is induced at similar levels by both low and high doses of doxorubicin, as well as by low and high concentrations of nutlin-3a [8]. In this scenario, the accumulation of TP53 beyond a low threshold would activate CDKN1A-mediated senescence (Figure 1A), whereas high levels of TP53 would be required for the ignition of a senescence-suppressing program that (once started) would always prevail over the effects of CDKN1A (Figure 1B).


TP53 and MTOR crosstalk to regulate cellular senescence.

Galluzzi L, Kepp O, Kroemer G - Aging (Albany NY) (2010)

TP53 levels determine whether CDKN1A will orchestrate irreversible senescence or quiescence.(A) Low doses of doxorubicin are sufficient to trigger TP53-mediated transactivation of the cell cycle-arresting protein CDKN1A. Under conditions in which the MTOR pathway is active, prolonged cell cycle arrest results in irreversible senescence. (B) High doxorubicin concentrations (or nutlin-3a alone or in combination with low doses of doxorubicin) not only drive TP53-mediated CDKN1A transactivation but might also result in the induction of one (or more) senescence-suppressing factors. In this scenario, MTOR activity is suppressed and CDKN1A-mediated cell cycle arrest is reversible (quiescence). By pharmacologically inhibiting MTOR, rapamycin also exerts senescence-suppressing functions.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2984599&req=5

Figure 1: TP53 levels determine whether CDKN1A will orchestrate irreversible senescence or quiescence.(A) Low doses of doxorubicin are sufficient to trigger TP53-mediated transactivation of the cell cycle-arresting protein CDKN1A. Under conditions in which the MTOR pathway is active, prolonged cell cycle arrest results in irreversible senescence. (B) High doxorubicin concentrations (or nutlin-3a alone or in combination with low doses of doxorubicin) not only drive TP53-mediated CDKN1A transactivation but might also result in the induction of one (or more) senescence-suppressing factors. In this scenario, MTOR activity is suppressed and CDKN1A-mediated cell cycle arrest is reversible (quiescence). By pharmacologically inhibiting MTOR, rapamycin also exerts senescence-suppressing functions.
Mentions: Based on the fascinating results obtained by Leontieva et al. [8], it can be speculated that nuclear TP53 might simultaneously transactivate the cell cycle-arresting factor CDKN1A and one or more hitherto unidentified anti-senescence (and perhaps pro-autophagic?) protein(s) that would operate similar to rapamycin, through the inhibition of MTOR. How would then the senescence-inducing activity of TP53 prevail over TP53-mediated senescence suppression (and vice versa)? As a possibility, the promoter of CDKN1Amight display a high affinity for TP53, while the promoter of the TP53 target that suppresses MTOR activity might require high TP53 concentrations for efficient transactivation. This hypothesis takes into consideration the fact that CDKN1A is induced at similar levels by both low and high doses of doxorubicin, as well as by low and high concentrations of nutlin-3a [8]. In this scenario, the accumulation of TP53 beyond a low threshold would activate CDKN1A-mediated senescence (Figure 1A), whereas high levels of TP53 would be required for the ignition of a senescence-suppressing program that (once started) would always prevail over the effects of CDKN1A (Figure 1B).

Bottom Line: The full spectrum of activities of the tumor suppressor p53 (TP53) has not been completely elucidated yet.Recently, it was demonstrated that TP53 communicates with the metabolic regulator mechanistic target of rapamycin (MTOR) to determine whether stressed cells undergo cell death, reversible quiescence or irreversible senescence, thereby adding yet another level of complexity to the signaling network that emanate from TP53.

View Article: PubMed Central - PubMed

ABSTRACT
The full spectrum of activities of the tumor suppressor p53 (TP53) has not been completely elucidated yet. Recently, it was demonstrated that TP53 communicates with the metabolic regulator mechanistic target of rapamycin (MTOR) to determine whether stressed cells undergo cell death, reversible quiescence or irreversible senescence, thereby adding yet another level of complexity to the signaling network that emanate from TP53.

Show MeSH
Related in: MedlinePlus