Activation of cAMP Signaling Interferes with Stress-Induced p53 Accumulation in ALL-Derived Cells by Promoting the Interaction between p53 and HDM2

Naderi, Elin Hallan; Jochemsen, Aart G.; Blomhoff, Heidi Kiil; Naderi, Soheil

doi:10.1593/neo.11542

Cited by 25 publications

(29 citation statements)

References 66 publications

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“…We have previously shown that this inhibitory effect of cAMP is mediated through its ability to abrogate the DNA damage-induced p53-HDM2 dissociation, leading to restoration of p53 degradation in DNA-damaged cells (17). Here, we provide evidence for the mechanism by which cAMP promotes the interaction of p53 with HDM2 and thereby prevents DNA damage-induced cell death.…”

Section: Discussionmentioning

confidence: 62%

“…We have shown that cAMP abrogates the DNA damage-induced stabilization of p53 by promoting its interaction with HDM2 (17). This, together with the finding that p53 acetylation has an inhibitory effect on its association with HDM2 (6,25) suggested deacetylation of p53 as the mechanism by which cAMP enhances the p53-HDM2 interaction in IR-treated cells.…”

Section: Camp Facilitates P53-hdm2 Binding Through P53 Acetylationmentioning

confidence: 61%

“…Our lab has previously reported that elevation of cAMP in lymphoid cells leads to arrest in the G1 phase of the cell cycle (12)(13)(14), arrest in the S phase and inhibition of apoptosis by anticancer agents (15). Using B cell precursor acute lymphoblastic leukaemia (BCP-ALL) cells as a model system, we also reported that the inhibitory effect of cAMP on apoptosis is p53-dependent (16), and that cAMP antagonizes the disruption of p53-HDM2 interaction by DNA damage (17). It was therefore of interest to further investigate the mechanism by which cAMP abolishes IR-induced p53 stability and apoptosis in these cells, and in particular, reveal how cAMP signaling promotes the interaction between p53 and HDM2.…”

Section: Introductionmentioning

confidence: 87%

“…Our recent result showing that cAMP has only a slight inhibitory effect on the IR-mediated phosphorylation of p53 (17), suggested that inhibition of acetylation might account for the ability of cAMP to reduce the IR-induced acidification of p53. To assess this assumption, Reh cells that were exposed to IR in the absence or presence of forskolin were harvested at 4 h post-IR and subjected to immunoblot analysis with antibodies specific for p53 acetylated at K373 and K382.…”

Section: Camp Inhibits P53 Accumulation and Isoelectric Point Shift Imentioning

confidence: 94%

“…We have previously shown that stimulation of cAMP signalling inhibits DNA damage-induced accumulation of p53 by facilitating its interaction with HDM2 (17). Because the interaction between p53 and HDM2 is known to be regulated by post-translational modifications of p53, we decided to examine whether cAMP affected the post-translational modifications of p53 in IR-treated cells.…”

Section: Camp Inhibits P53 Accumulation and Isoelectric Point Shift Imentioning

confidence: 99%

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cAMP signalling inhibits p53 acetylation and apoptosis via HDAC and SIRT deacetylases

Kloster

Naderi

Haaland

et al. 2013

International Journal of Oncology

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Abstract. Activation of cAMP signalling potently inhibits DNA damage-induced apoptosis in acute lymphoblastic leukemia cells by promoting the turnover of p53 protein. Recently, we showed that the cAMP-induced destabilization of p53 in DNA-damaged cells occurs as a result of enhanced interaction between p53 and HDM2. In this report, we present results showing that increased levels of cAMP in cells with DNA damage enhances the deacetylation of p53, an event that facilitates the interaction of p53 with HDM2, thus annulling the stabilizing effect of DNA damage on p53. The combined inhibition of the HDAC and SIRT1 deacetylases abolished the cAMP-mediated deacetylation of p53, implying that cAMP-mediated deacetylation of p53 is dependent on the activity of these two classes of histone deacetylases. Importantly, diminishing the activity of HDACs and SIRT1 was also found to reverse the inhibitory effect of cAMP on the DNA damage-induced p53 stabilization and apoptosis, suggesting the involvement of the p53 acetylation pathway in the anti-apoptotic effect of cAMP signalling.

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Section: Discussionmentioning

confidence: 62%

Section: Camp Facilitates P53-hdm2 Binding Through P53 Acetylationmentioning

confidence: 61%

Section: Introductionmentioning

confidence: 87%

Section: Camp Inhibits P53 Accumulation and Isoelectric Point Shift Imentioning

confidence: 94%

Section: Camp Inhibits P53 Accumulation and Isoelectric Point Shift Imentioning

confidence: 99%

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cAMP signalling inhibits p53 acetylation and apoptosis via HDAC and SIRT deacetylases

Kloster

Naderi

Haaland

et al. 2013

International Journal of Oncology

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Prostaglandin EP2 receptor signaling protects human trabecular meshwork cells from apoptosis induced by ER stress through down-regulation of p53

Kalouche

Boucher

Coste

et al. 2016

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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E-prostanoid receptor subtype 2 (EP2) agonists are currently under clinical development as hypotensive agents for the treatment of ocular hypertension. However, the effects of EP2 receptor agonists on trabecular meshwork (TM) alterations leading to primary open-angle glaucoma (POAG) are still unknown. Here, we evaluated whether EP2 receptor activation exhibits protective functions on TM cell death induced by endoplasmic reticulum (ER) stress. We show that the EP2 receptor agonist butaprost protects TM cell death mediated by the ER stress inducer tunicamycin through a cyclic AMP (cAMP)-dependent mechanism, but independent of the classical cAMP sensors, protein kinase A and exchange proteins activated by cAMP. The ER stress-induced intrinsic apoptosis inhibited by the EP2 receptor agonist was correlated with a decreased accumulation of the cellular stress sensor p53. In addition, p53 down-regulation was associated with inhibition of its transcriptional activity, which led to decreased expression of the pro-apoptotic p53-upregulated modulator of apoptosis (PUMA). The stabilization of p53 by nutlin-3a abolished butaprost-mediated cell death protection. In conclusion, we showed that EP2 receptor activation protects against ER stress-dependent mitochondrial apoptosis through down-regulation of p53. The specific inhibition of this pathway could reduce TM alterations observed in POAG patients.

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cAMP protects acute promyelocytic leukemia cells from arsenic trioxide-induced caspase-3 activation and apoptosis

Safa

Mousavizadeh

Noori

et al. 2014

European Journal of Pharmacology

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Activation of cAMP Signaling Interferes with Stress-Induced p53 Accumulation in ALL-Derived Cells by Promoting the Interaction between p53 and HDM2

Cited by 25 publications

References 66 publications

cAMP signalling inhibits p53 acetylation and apoptosis via HDAC and SIRT deacetylases

cAMP signalling inhibits p53 acetylation and apoptosis via HDAC and SIRT deacetylases

Prostaglandin EP2 receptor signaling protects human trabecular meshwork cells from apoptosis induced by ER stress through down-regulation of p53

cAMP protects acute promyelocytic leukemia cells from arsenic trioxide-induced caspase-3 activation and apoptosis

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