A p53-derived apoptotic peptide derepresses p73 to cause tumor regression in vivo

Bell, Helen; Dufès, Christine; O’Prey, Jim; Crighton, Diane; Bergamaschi, Daniele; Lü, Xin; Schätzlein, Andreas; Vousden, Karen H.; Ryan, Kevin M.

doi:10.1172/jci28920

Cited by 71 publications

(80 citation statements)

References 45 publications

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“…pShuttle constructs were then recombined into pAdEasy and were subsequently amplified as previously described. 34,35 Adenoviruses were titered using AdEasy TM Viral Titer Kit (Stratagene, 972500). Equal numbers of infective particles were used for each splice variant in comparative studies.…”

Section: Methodsmentioning

confidence: 99%

DRAM-1 encodes multiple isoforms that regulate autophagy

et al. 2012

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Keywords: DRAM-1, mRNA splice variants, p53, cell death, autophagy Abbreviations: RNAi, RNA interference; siRNA, small interfering RNA; GFP, green fluorescent protein; LC3, microtubule-associated protein 1 light chain 3; SV, splice variant; DRAM-1, damage-regulated autophagy modulator-1; MEF, mouse embryo fibroblast; Dox, doxycyclineMacro(autophagy) is a cellular mechanism which delivers cytoplasmic constituents to lysosomes for degradation. Due to its role in maintaining cellular integrity, autophagy protects against various diseases including cancer. p53 is a major tumor suppressor gene which can modulate autophagy both positively and negatively. p53 induces autophagy via transcriptional activation of damage-regulated autophagy modulator (DRAM-1). We report here that DRAM-1 encodes not just one mRNA, but a series of p53-inducible splice variants which are expressed at varying levels in multiple human and mouse cell lines. Two of these new splice variants, termed SV4 and SV5, result in mature mRNA species. Different from 'full-length' DRAM-1 (SV1), SV4 and SV5 do not localize to lysosomes or endosomes, but instead partially localize to peroxisomes and autophagosomes respectively. In addition, SV4 and SV5 can also be found co-localized with certain markers of the endoplasmic reticulum. Similar to SV1, SV4 and SV5 do not appear to be inducers of programmed cell death, but they do modulate autophagy. In summary, these findings identify new autophagy regulators that provide insight into the control of autophagy downstream of p53.

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Section: Methodsmentioning

confidence: 99%

DRAM-1 encodes multiple isoforms that regulate autophagy

et al. 2012

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“…100 Notably, iASPP also binds and inhibits p73; expression of a peptide displacing the iASPP-p73 interaction was shown to promote p73-dependent apoptosis in transformed cells lacking p53. 101 Therefore, cellular levels of ASPP proteins, differentially affecting all p53-family proteins, may be a crucial parameter in determining the apoptotic readout of the p53 pathway. Not surprisingly, altered expression of ASPP genes is a frequent event in tumors.…”

Section: And References Therein)mentioning

confidence: 99%

p53-family proteins and their regulators: hubs and spokes in tumor suppression

2010

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The tumor suppressor p53 is a central hub in a molecular network controlling cell proliferation and death in response to potentially oncogenic conditions, and a wide array of covalent modifications and protein interactions modulate the nuclear and cytoplasmic activities of p53. The p53 relatives, p73 and p63, are entangled in the same regulatory network, being subject at least in part to the same modifications and interactions that convey signals on p53, and actively contributing to the resulting cellular output. The emerging picture is that of an interconnected pathway, in which all p53-family proteins are involved in the response to oncogenic stress and physiological inputs. Therefore, common and specific interactors of p53-family proteins can have a wide effect on function and dysfunction of this pathway. Many years of research have uncovered an impressive number of p53-interacting proteins, but much less is known about protein interactions of p63 and p73. Yet, many interactors may be shared by multiple p53-family proteins, with similar or different effects. In this study we review shared interactors of p53-family proteins with the aim to encourage research into this field; this knowledge promises to unveil regulatory elements that could be targeted by a new generation of molecules, and allow more efficient use of currently available drugs for cancer treatment.

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“…Still, a number of p53 mutant proteins can associate with p63 and p73, blocking their transcriptional activity and thus contributing to the malignant phenotype of cancer cells (9)(10)(11). Activation of p73 in human cancer can produce substantial cytotoxic effect even in the cells lacking p53 (12)(13)(14)(15)(16), which allows considering p73 as a separate anticancer drug target. We decided to search for small molecules that release suppressor activities of the p53 family members blocked by mutant p53.…”

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confidence: 99%

Small-molecule RETRA suppresses mutant p53-bearing cancer cells through a p73-dependent salvage pathway

Kravchenko

Ilyinskaya

Komarov

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

172

140

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Identification of unique features of cancer cells is important for defining specific and efficient therapeutic targets. Mutant p53 is present in nearly half of all cancer cases, forming a promising target for pharmacological reactivation. In addition to being defective for the tumor-suppressor function, mutant p53 contributes to malignancy by blocking a p53 family member p73. Here, we describe a small-molecule RETRA that activates a set of p53-regulated genes and specifically suppresses mutant p53-bearing tumor cells in vitro and in mouse xenografts. Although the effect is strictly limited to the cells expressing mutant p53, it is abrogated by inhibition with RNAi to p73. Treatment of mutant p53-expressing cancer cells with RETRA results in a substantial increase in the expression level of p73, and a release of p73 from the blocking complex with mutant p53, which produces tumor-suppressor effects similar to the functional reactivation of p53. RETRA is active against tumor cells expressing a variety of p53 mutants and does not affect normal cells. The results validate the mutant p53-p73 complex as a promising and highly specific potential target for cancer therapy.cancer therapy ͉ p73 family ͉ tumor suppressors

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A p53-derived apoptotic peptide derepresses p73 to cause tumor regression in vivo

Cited by 71 publications

References 45 publications

DRAM-1 encodes multiple isoforms that regulate autophagy

DRAM-1 encodes multiple isoforms that regulate autophagy

p53-family proteins and their regulators: hubs and spokes in tumor suppression

Small-molecule RETRA suppresses mutant p53-bearing cancer cells through a p73-dependent salvage pathway

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