Reactivation of Mutant p53 and Induction of Apoptosis in Human Tumor Cells by Maleimide Analogs

Bykov, Vladimir J.N.; Issaeva, Natalia; Zache, Nicole; Shilov, A. A.; Hultcrantz, Monica; Bergman, Jan; Selivanova, Galina; Wiman, Klas G.

doi:10.1074/jbc.m501664200

Cited by 211 publications

(110 citation statements)

References 31 publications

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“…3B). We noticed that both drugs exerted a significant inhibition of mRNA translation compared with untreated cells as indicated by the increase in ribosomal subunit peaks (compare fractions 5-11 to control) concomitant with a significant decrease of the largest class of polyribosomes (fractions [12][13][14][15][16][17][18][19][20]. Under these conditions ATF4 mRNA translation was induced further demonstrating the dependence of this mRNA on eIF2␣ phosphorylation for efficient translation (Fig.…”

Section: Activation Of Eif2␣ Kinases Results In P53mentioning

confidence: 99%

“…The current interest in p53 is underscored by the tremendous therapeutic benefits of its reactivation in cancer cells. Small molecules or peptides that restore the function of mutant p53 proteins have a great anti-tumor potential by enhancing the apoptotic sensitivity of tumor cells (11)(12)(13). Because p53 activity is influenced by many factors, targeting of proteins that regulate p53 function may also be necessary to ensure its ability to switch on its apoptotic programs (1,6).…”

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confidence: 99%

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The eIF2α Kinases PERK and PKR Activate Glycogen Synthase Kinase 3 to Promote the Proteasomal Degradation of p53

Baltzis¹,

Pluquet²,

Papadakis

et al. 2007

Journal of Biological Chemistry

106

101

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Phosphorylation of eukaryotic initiation factor 2␣ (eIF2␣) is mediated by a family of kinases that respond to various forms of environmental stress. The eIF2␣ kinases are critical for mRNA translation, cell proliferation, and apoptosis. Activation of the tumor suppressor p53 results in cell cycle arrest and apoptosis in response to various types of stress. We previously showed that, unlike the majority of stress responses that stabilize and activate p53, induction of endoplasmic reticulum stress leads to p53 degradation through an Mdm2-dependent mechanism. Here, we demonstrate that the endoplasmic reticulum-resident eIF2␣ kinase PERK mediates the proteasomal degradation of p53 independently of translational control. This role is not specific for PERK, because the eIF2␣ kinase PKR also promotes p53 degradation in response to double-stranded RNA. We further establish that the eIF2␣ kinases induce glycogen synthase kinase 3 to promote the nuclear export and proteasomal degradation of p53. Our findings reveal a novel cross-talk between the eIF2␣ kinases and p53 with implications in cell proliferation and tumorigenesis.The tumor suppressor p53 is a transcription factor mutated in ϳ50% of human cancers (1). In normal cells, p53 plays a pivotal role in controlling cell cycle, apoptosis, and DNA repair in response to various forms of genotoxic stress (2, 3). The regulation of p53 is complex and occurs mainly at the post-translational level (4). This is mediated by various post-translational modifications, such as phosphorylation and acetylation, which contribute to its stabilization and activation (5). The stability of p53 is regulated by its interaction with Hdm2 (human Mdm2), an E3-ubiquitin ligase that acts as an antagonist limiting p53 tumor suppressor function (6). Both p53 and Hdm2 are in an autoregulatory feedback loop in which p53 induces Hdm2 expression at the transcriptional level. The Hdm2 protein then binds to and ubiquitinates p53 in the nucleus, a process that allows the nuclear export and the cytoplasmic proteasome-dependent degradation of the tumor suppressor (6). In addition to Hdm2, other ubiquitin ligases, such as COP1 (7) and Pirh2 (8), have been shown to disrupt p53 stability. However, compared with Hdm2, little is currently known about how these ligases act on p53 (9).The majority of stress responses that activate p53 require its nuclear accumulation and function (10). This is mediated mainly through inactivation of the Hdm2-dependent degradation pathway as well as through interactions with nuclear proteins that promote post-translational modifications of p53 leading to its stabilization and activation (10). The current interest in p53 is underscored by the tremendous therapeutic benefits of its reactivation in cancer cells. Small molecules or peptides that restore the function of mutant p53 proteins have a great anti-tumor potential by enhancing the apoptotic sensitivity of tumor cells (11-13). Because p53 activity is influenced by many factors, targeting of proteins that regulate p53 function may...

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Section: Activation Of Eif2␣ Kinases Results In P53mentioning

confidence: 99%

mentioning

confidence: 99%

The eIF2α Kinases PERK and PKR Activate Glycogen Synthase Kinase 3 to Promote the Proteasomal Degradation of p53

Baltzis¹,

Pluquet²,

Papadakis

et al. 2007

Journal of Biological Chemistry

106

101

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“…Small molecules such as PRIMA-1,62 CP3139863 and MIRA-1,64 that can activate mutant p53 in cell-based assays have already been identified (figure 1). Small peptide activators of mutant p53 have also been shown to be effective in animal models,65 however, the mechanism by which these compounds restore wild type conformation is still unclear.…”

Section: Attempts To Reactivate Mutant P53mentioning

confidence: 99%

“…MIRA-1, a maleimide analogue, induces apoptosis in mutant p53 cells via restoration of p53-dependent transcriptional transactivation 64. Using sarcoma and lung carcinoma cell lines, Bykov et al 64 described that MIRA-1 acted by shifting the equilibrium between the native and unfolded conformation of p53 towards the native conformation, leading to restoration of p53-mediated transactivation of target genes and induction of apoptosis in a mutant p53-dependent manner.…”

Section: Attempts To Reactivate Mutant P53mentioning

confidence: 99%

Pharmacological activation of the p53 pathway in haematological malignancies

et al. 2009

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p53 gene mutations are rarely detected at diagnosis in common haematological cancers such as multiple myeloma (MM), acute myeloid leukaemia (AML), chronic lymphocytic leukaemia (CLL) and Hodgkin's disease (HD), although their prevalence may increase with progression to more aggressive or advanced stages. Therapeutic induction of p53 might therefore be particularly suitable for the treatment of haematological malignancies. Some of the anti-tumour activity of current chemotherapeutics has been derived from activation of p53. However, until recently it was unknown whether p53 signalling is functional in certain haematological cancers including MM and if p53 activity is sufficient to trigger an apoptotic response. With the recent discovery of nutlins, which represent the first highly selective small molecule inhibitors of the p53-MDM2 interaction, pharmacological tools are now available to induce p53 irrespective of upstream signalling defects, and to functionally analyse the downstream p53 pathway in primary leukaemia and lymphoma cells. Combination therapy is emerging as a key factor, and development of non-genotoxic combinations seems very promising for tackling the problems of toxicity and resistance. This review will highlight recent findings in the research into molecules capable of modulating p53 protein activities and mechanisms that activate the p53 pathway, restoring response to therapy in haematological malignancies.

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“…59 These compounds are structurally different from PRIMA-1 but have similar potency and mutant p53 selectivity in cellular assays. However, MIRA-1 appears to reactivate a narrower range of mutants than PRIMA-1.…”

Section: Reactivation Of Mutant P53mentioning

confidence: 99%