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MDM2 turnover and expression of ATRX determine the choice between quiescence and senescence in response to CDK4 inhibition.

Kovatcheva M, Liu DD, Dickson MA, Klein ME, O'Connor R, Wilder FO, Socci ND, Tap WD, Schwartz GK, Singer S, Crago AM, Koff A - Oncotarget (2015)

Bottom Line: Failure to reduce MDM2 does not prevent CDK4i-induced withdrawal from the cell cycle but the cells remain in a reversible quiescent state.CDK4i-induced senescence associated with loss of MDM2 is also observed in some breast cancer, lung cancer and glioma cell lines indicating that this is not limited to WD/DDLS cells in which MDM2 is overexpressed or in cells that contain wild type p53.Interestingly, in seven patients the changes in MDM2 expression were correlated with outcome.

View Article: PubMed Central - PubMed

Affiliation: The Louis V. Gerstner Graduate School of Biomedical Sciences, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, USA.

ABSTRACT
CDK4 inhibitors (CDK4i) earned Breakthrough Therapy Designation from the FDA last year and are entering phase III clinical trials in several cancers. However, not all tumors respond favorably to these drugs. CDK4 activity is critical for progression through G1 phase and into the mitotic cell cycle. Inhibiting this kinase induces Rb-positive cells to exit the cell cycle into either a quiescent or senescent state. In this report, using well-differentiated and dedifferentiated liposarcoma (WD/DDLS) cell lines, we show that the proteolytic turnover of MDM2 is required for CDK4i-induced senescence. Failure to reduce MDM2 does not prevent CDK4i-induced withdrawal from the cell cycle but the cells remain in a reversible quiescent state. Reducing MDM2 in these cells drives them into the more stable senescent state. CDK4i-induced senescence associated with loss of MDM2 is also observed in some breast cancer, lung cancer and glioma cell lines indicating that this is not limited to WD/DDLS cells in which MDM2 is overexpressed or in cells that contain wild type p53. MDM2 turnover depends on its E3 ligase activity and expression of ATRX. Interestingly, in seven patients the changes in MDM2 expression were correlated with outcome. These insights identify MDM2 and ATRX as new regulators controlling geroconversion, the process by which quiescent cells become senescent, and this insight may be exploited to improve the activity of CDK4i in cancer therapy.

No MeSH data available.


Related in: MedlinePlus

SummaryAs described in the text, PD0332991 can induce cell cycle exit accompanied by the dissociation of HAUSP from MDM2. Geroconversion, or the transition of cells to senescence, indicated by the red arrow, is dependent on proteosomal degradation of MDM2 and expression of ATRX. p53-independent mechanisms can contribute to senescence induced by CDK4 inhibition and MDM2 knockdown.
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Figure 9: SummaryAs described in the text, PD0332991 can induce cell cycle exit accompanied by the dissociation of HAUSP from MDM2. Geroconversion, or the transition of cells to senescence, indicated by the red arrow, is dependent on proteosomal degradation of MDM2 and expression of ATRX. p53-independent mechanisms can contribute to senescence induced by CDK4 inhibition and MDM2 knockdown.

Mentions: As summarized in Figure 9, our data indicate that geroconversion depends on the accelerated rate of MDM2 turnover following the dissociation of the deubiquitinase HAUSP from MDM2. CDK4 inhibition induces cell cycle exit and this primes cells for MDM2 auto-ubiquitination, however, something in non-responder cells is preventing this. Intriguingly, expression of the chromatin-remodeling enzyme ATRX is also important for geroconversion. Because ATRX deficiency prevents the loss of MDM2 we hypothesize that ATRX directly regulates a program that impinges on MDM2 regulation. Furthermore, because the phosphorylation of ATRX at serine 2487 is associated with the inability of cells to undergo geroconversion following CDK4 inhibition, we suspect that this modification affects this activity. More detailed mechanistic studies can examine each part of this model in the future as discussed below.


MDM2 turnover and expression of ATRX determine the choice between quiescence and senescence in response to CDK4 inhibition.

Kovatcheva M, Liu DD, Dickson MA, Klein ME, O'Connor R, Wilder FO, Socci ND, Tap WD, Schwartz GK, Singer S, Crago AM, Koff A - Oncotarget (2015)

SummaryAs described in the text, PD0332991 can induce cell cycle exit accompanied by the dissociation of HAUSP from MDM2. Geroconversion, or the transition of cells to senescence, indicated by the red arrow, is dependent on proteosomal degradation of MDM2 and expression of ATRX. p53-independent mechanisms can contribute to senescence induced by CDK4 inhibition and MDM2 knockdown.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4480747&req=5

Figure 9: SummaryAs described in the text, PD0332991 can induce cell cycle exit accompanied by the dissociation of HAUSP from MDM2. Geroconversion, or the transition of cells to senescence, indicated by the red arrow, is dependent on proteosomal degradation of MDM2 and expression of ATRX. p53-independent mechanisms can contribute to senescence induced by CDK4 inhibition and MDM2 knockdown.
Mentions: As summarized in Figure 9, our data indicate that geroconversion depends on the accelerated rate of MDM2 turnover following the dissociation of the deubiquitinase HAUSP from MDM2. CDK4 inhibition induces cell cycle exit and this primes cells for MDM2 auto-ubiquitination, however, something in non-responder cells is preventing this. Intriguingly, expression of the chromatin-remodeling enzyme ATRX is also important for geroconversion. Because ATRX deficiency prevents the loss of MDM2 we hypothesize that ATRX directly regulates a program that impinges on MDM2 regulation. Furthermore, because the phosphorylation of ATRX at serine 2487 is associated with the inability of cells to undergo geroconversion following CDK4 inhibition, we suspect that this modification affects this activity. More detailed mechanistic studies can examine each part of this model in the future as discussed below.

Bottom Line: Failure to reduce MDM2 does not prevent CDK4i-induced withdrawal from the cell cycle but the cells remain in a reversible quiescent state.CDK4i-induced senescence associated with loss of MDM2 is also observed in some breast cancer, lung cancer and glioma cell lines indicating that this is not limited to WD/DDLS cells in which MDM2 is overexpressed or in cells that contain wild type p53.Interestingly, in seven patients the changes in MDM2 expression were correlated with outcome.

View Article: PubMed Central - PubMed

Affiliation: The Louis V. Gerstner Graduate School of Biomedical Sciences, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, USA.

ABSTRACT
CDK4 inhibitors (CDK4i) earned Breakthrough Therapy Designation from the FDA last year and are entering phase III clinical trials in several cancers. However, not all tumors respond favorably to these drugs. CDK4 activity is critical for progression through G1 phase and into the mitotic cell cycle. Inhibiting this kinase induces Rb-positive cells to exit the cell cycle into either a quiescent or senescent state. In this report, using well-differentiated and dedifferentiated liposarcoma (WD/DDLS) cell lines, we show that the proteolytic turnover of MDM2 is required for CDK4i-induced senescence. Failure to reduce MDM2 does not prevent CDK4i-induced withdrawal from the cell cycle but the cells remain in a reversible quiescent state. Reducing MDM2 in these cells drives them into the more stable senescent state. CDK4i-induced senescence associated with loss of MDM2 is also observed in some breast cancer, lung cancer and glioma cell lines indicating that this is not limited to WD/DDLS cells in which MDM2 is overexpressed or in cells that contain wild type p53. MDM2 turnover depends on its E3 ligase activity and expression of ATRX. Interestingly, in seven patients the changes in MDM2 expression were correlated with outcome. These insights identify MDM2 and ATRX as new regulators controlling geroconversion, the process by which quiescent cells become senescent, and this insight may be exploited to improve the activity of CDK4i in cancer therapy.

No MeSH data available.


Related in: MedlinePlus