MDM2-Dependent Downregulation of p21 and hnRNP K Provides a Switch between Apoptosis and Growth Arrest Induced by Pharmacologically Activated p53

Enge, Martin; Bao, Wenjie; Hedström, Elisabeth; Jackson, Stephen; Moumen, Abdeladim; Selivanova, Galina

doi:10.1016/j.ccr.2009.06.012

Cited by 33 publications

(63 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A recent study published in the course of this study has reported that p21 downregulation by siRNA enhances the apoptotic response to nutlin-3 (Enge et al, 2009). This conclusion was based on limited experiments with a single cell line, HCT116.…”

Section: Discussionmentioning

confidence: 67%

p21 does not protect cancer cells from apoptosis induced by nongenotoxic p53 activation

2010

View full text Add to dashboard Cite

p21 Waf1/Cip1 is a p53 transcription target implicated in both major functions of the tumor suppressor-cell cycle arrest and apoptosis. It is a potent inhibitor of the key cyclindependent kinases (CDK1-4), and has been thought to be the main mediator of p53-dependent G1 and G2 arrest. However, an increasing body of information suggests that in addition to its cell-cycle inhibitory activity, p21 can affect p53-dependent apoptosis. These data have been obtained from experiments in which p53 is activated primarily by genotoxic stress. In this study, we use the selective MDM2 antagonist, nutlin-3a, as a nongenotoxic p53 activator and show that the cell-cycle arrest function of p21 is dependent on the cellular context. In most cancer cell lines, p53-dependent p21 induction is essential for cellcycle arrest, but in some, p21 is dispensable. Depletion of p21 did not increase the apoptotic response to nutlin-3a in all seven cancer cell lines tested and p21 overexpression did not protect apoptosis-sensitive lines from death. p21 was found to mediate nutlin-induced p53-dependent downregulation of another antiapoptotic protein, survivin, without significantly affecting the apoptotic outcome. Taken together our results suggest that p21 induction does not affect the apoptotic response to nongenotoxic p53 activation.

show abstract

Section: Discussionmentioning

confidence: 67%

p21 does not protect cancer cells from apoptosis induced by nongenotoxic p53 activation

2010

View full text Add to dashboard Cite

show abstract

“…Comparison of the biological effects of two inhibitors of the p53/Hdm2 interaction, nutlin3a and RITA showed that in HCT116 and MCF7 cells, RITA induces apoptosis whereas nutlin3a triggers mainly growth arrest. 27,28 Several studies have demonstrated that HdmX impedes the induction of apoptosis upon inhibition of Hdm2 by nutlin3a in MCF7 cells. We found that HdmX is potently downregulated after RITA treatment, but not after nutlin3a treatment (Figures 1a and 5c).…”

Section: Resultsmentioning

confidence: 99%

Abrogation of Wip1 expression by RITA-activated p53 potentiates apoptosis induction via activation of ATM and inhibition of HdmX

Spinnler

Hedström

et al. 2011

Cell Death Differ

View full text Add to dashboard Cite

Inactivation of the p53 tumour suppressor, either by mutation or by overexpression of its inhibitors Hdm2 and HdmX is the most frequent event in cancer. Reactivation of p53 by targeting Hdm2 and HdmX is therefore a promising strategy for therapy. However, Hdm2 inhibitors do not prevent inhibition of p53 by HdmX, which impedes p53-mediated apoptosis. Here, we show that p53 reactivation by the small molecule RITA leads to efficient HdmX degradation in tumour cell lines of different origin and in xenograft tumours in vivo. Notably, HdmX degradation occurs selectively in cancer cells, but not in non-transformed cells. We identified the inhibition of the wild-type p53-induced phosphatase 1 (Wip1) as the major mechanism important for full engagement of p53 activity accomplished by restoration of the ataxia telangiectasia mutated (ATM) kinase-signalling cascade, which leads to HdmX degradation. In contrast to previously reported transactivation of Wip1 by p53, we observed p53-dependent repression of Wip1 expression, which disrupts the negative feedback loop conferred by Wip1. Our study reveals that the depletion of both HdmX and Wip1 potentiates cell death due to sustained activation of p53. Thus, RITA is an example of a p53-reactivating drug that not only blocks Hdm2, but also inhibits two important negative regulators of p53 -HdmX and Wip1, leading to efficient elimination of tumour cells.

show abstract

“…5,21 We analyzed the levels of several p53 target genes in response to RITA in different Figure 5 The rapid replication block in response to RITA treatment is p53 and Chk2 dependent. (a) HCT116 p53 þ / þ , p53 À/À and Chk2 À/À cells were treated with RITA for the indicated periods.…”

Section: Resultsmentioning

confidence: 99%

“…On the other hand, RITA does not induce G1 arrest, but in general is more capable of inducing apoptosis. 5 The mechanistic properties of RITA seem complex. RITA was proposed to induce a conformational change in p53 that prevents its binding to Hdm2.…”

mentioning

confidence: 99%

“…RITA was proposed to induce a conformational change in p53 that prevents its binding to Hdm2. 2 NMR studies did not support this mechanism, 6 but a later study suggested a role for the released pool of Hdm2 to promote degradation of p21 and the p53 cofactor hnRNP K. 5 Furthermore, induction of proapoptotic homeodomain-interacting protein kinase-2 levels, 7 inhibition of pro-survival TrxR1 activity 8 and reduced expression of Wip1 phosphatase and Hdmx 9 have been described as contributing to RITA effects. RITA has also been implicated in the inhibition of angiogenesis-promoting hypoxia-induced factor-1a protein synthesis by increasing the phosphorylation of eukaryotic initiation factor 2a.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Chk2 mediates RITA-induced apoptosis

et al. 2011

View full text Add to dashboard Cite

Reactivation of the p53 tumor-suppressor protein by small molecules like Nutlin-3 and RITA (reactivation of p53 and induction of tumor cell apoptosis) is a promising strategy for cancer therapy. The molecular mechanisms involved in the responses to RITA remain enigmatic. Several groups reported the induction of a p53-dependent DNA damage response. Furthermore, the existence of a p53-dependent S-phase checkpoint has been suggested, involving the checkpoint kinase Chk1. We have recently shown synergistic induction of apoptosis by RITA in combination with Nutlin-3, and we observed concomitant Chk2 phosphorylation. Therefore, we investigated whether Chk2 contributes to the cellular responses to RITA. Strikingly, the induction of apoptosis seemed entirely Chk2 dependent. Transcriptional activity of p53 in response to RITA required the presence of Chk2. A partial rescue of apoptosis observed in Noxa knockdown cells emphasized the relevance of p53 transcriptional activity for RITAinduced apoptosis. In addition, we observed an early p53-and Chk2-dependent block of DNA replication upon RITA treatment. Replicating cells seemed more prone to entering RITA-induced apoptosis. Furthermore, the RITA-induced DNA damage response, which was not a secondary effect of apoptosis induction, was strongly attenuated in cells lacking p53 or Chk2.In conclusion, we identified Chk2 as an essential mediator of the cellular responses to RITA.

show abstract

MDM2-Dependent Downregulation of p21 and hnRNP K Provides a Switch between Apoptosis and Growth Arrest Induced by Pharmacologically Activated p53

Cited by 33 publications

References 0 publications

p21 does not protect cancer cells from apoptosis induced by nongenotoxic p53 activation

p21 does not protect cancer cells from apoptosis induced by nongenotoxic p53 activation

Abrogation of Wip1 expression by RITA-activated p53 potentiates apoptosis induction via activation of ATM and inhibition of HdmX

Chk2 mediates RITA-induced apoptosis

Contact Info

Product

Resources

About