Questioning the oncogenic role of ΔNp73α in different cell lines expressing p53 or not

Marrazzo, Eleonora; Marchini, Sergio; Previdi, Sara; Broggini, Massimo

doi:10.4161/cbt.5.7.2753

Cited by 10 publications

(6 citation statements)

References 27 publications

(37 reference statements)

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“…Thus, it is possible that in cases wherein ΔNp73 variants are predominantly expressed, MCL1 would act to negatively regulate their suppressive effects and thereby activate normal p73 function. In our cell models used for these studies, we were unable to detect endogenous ΔNp73 protein using commercially available antibodies, consistent with previous accounts using these cell lines, suggesting there is no detectable endogenous ΔNp73 present 54,55 . Therefore, our studies primarily focus on the impacts that MCL1 has on the pro-apoptotic transcriptional regulation by TAp73.…”

Section: Discussionsupporting

confidence: 89%

MCL1 binds and negatively regulates the transcriptional function of tumor suppressor p73

et al. 2020

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MCL1, an anti-apoptotic protein that controls chemosensitivity and cell fate through its regulation of intrinsic apoptosis, has been identified as a high-impact target in anti-cancer therapeutic development. With MCL1-specific inhibitors currently in clinical trials, it is imperative that we understand the roles that MCL1 plays in cells, especially when targeting the Bcl-2 homology 3 (BH3) pocket, the central region of MCL1 that mediates apoptotic regulation. Here, we establish that MCL1 has a direct role in controlling p73 transcriptional activity, which modulates target genes associated with DNA damage response, apoptosis, and cell cycle progression. This interaction is mediated through the reverse BH3 (rBH3) motif in the p73 tetramerization domain, which restricts p73 assembly on DNA. Here, we provide a novel mechanism for protein-level regulation of p73 transcriptional activity by MCL1, while also framing a foundation for studying MCL1 inhibitors in combination with platinum-based chemotherapeutics. More broadly, this work expands the role of Bcl-2 family signaling beyond cell fate regulation.

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Section: Discussionsupporting

confidence: 89%

MCL1 binds and negatively regulates the transcriptional function of tumor suppressor p73

et al. 2020

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“…The conclusion was that DNp73α overexpression was not sufficient per se to induce a more drug‐resistant phenotype 28. Similar results have been recently obtained in cancer cells not expressing p53 29. On the basis of the previous considerations, we proceeded to analyze of DNp73α's ability to cause transdominant inhibition of the tumor suppressor function of p53.…”

mentioning

confidence: 52%

In vivo evaluation of the role of DNp73α protein in regulating the p53‐dependent apoptotic pathway after treatment with cytotoxic drugs

Sabatino

Previdi

Broggini

2006

Intl Journal of Cancer

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The amino terminus truncated p73 isoform, DNp73a, shows dominant negative behavior toward TAp73 and wild-type p53, and has oncogenic potential. By contrast, we recently showed that in HCT116 clones forced expression of DNp73a did not increase in vitro cellular resistance to anticancer agents. The purpose of this study was to characterize in vivo models and to investigate the functional interaction between the DNp73a isoform and the p53 pathway. Human colon carcinoma HCT116 clones expressing inducible DNp73a (HCT116/DN3, HCT116/DN14) and HCT116/8a (transfected with the mock empty vector), transplanted in immunodeficient nude mice, were used to study the antitumor activity of cis-diammine-dichloro-platinum (cDDP) (4 mg/kg, i.v., q7d 3 3) and Doxorubicin (DX) (7.5 mg/kg, i.v., q7d 3 3), with or without tetracycline-induced DNp73a overexpression. DNp73a expression was confirmed by RT-PCR, immunoblotting and immunohistochemical analysis. DNp73a subcellular localization after DX treatment was checked by an immunofluorescence assay. Western blot was used to analyze p53, p21, Bax, Bcl-2 and p53AIP1 expression. DNp73a overexpression did not modify the antitumor activity of either DX or cDDP in xenograft models. DX reduced DNp73a protein expression, without affecting its nuclear localization. p53, p21, Bax and p53AIP1 protein expression increased and Bcl-2 decreased in HCT116 clone derived tumors 24 hr after DX exposure, independently of the presence of DNp73a. Overexpression of DNp73a does not affect tumor growth in vivo, does not increase the resistance of established tumors to anticancer agents and does not antagonize p53 apoptotic functions. ' 2006 Wiley-Liss, Inc.Key words: in vivo; colon carcinoma; DNp73a; p53; apoptosis In different in vivo and in vitro models, DNA damage or inappropriate oncogenic stimulation lead to stabilization and activation, mostly by post-translational modifications, of the p53 transcription factor, one of the main regulators of cell growth and an important factor in cellular sensitivity to anticancer agents. p53 activated protein induces downstream cascades of events that set in motion an elaborate network of cellular signals, not yet fully characterized, with autoregulatory positive or negative feedback loops, to coordinate cell-cycle arrest, DNA repair and/or apoptosis, and which finally results in preventing tumor growth and maintaining the integrity of the genome.

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“…In fact, various chemotherapeutic agents can induce ΔNp73 expression in neoplastic cell lines, suggesting a role in apoptotic response [52,53]. Others have noted that constitutive expression of ΔNp73 isoforms can either resist or increase apoptosis while inducing p53 target gene expression [54,55]. The pro-apoptotic effects of ΔNp73 have been previously described and may reflect cell type-dependent factors other than specific interactions with p53.…”

Section: Discussionmentioning

confidence: 99%

Overexpressed TP73 induces apoptosis in medulloblastoma

et al. 2007

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Background: Medulloblastoma is the most common malignant brain tumor of childhood. Children who relapse usually die of their disease, which reflects resistance to radiation and/or chemotherapy. Improvements in outcome require a better understanding of the molecular basis of medulloblastoma growth and treatment response. TP73 is a member of the TP53 tumor suppressor gene family that has been found to be overexpressed in a variety of tumors and mediates apoptotic responses to genotoxic stress. In this study, we assessed expression of TP73 RNA species in patient tumor specimens and in medulloblastoma cell lines, and manipulated expression of full-length TAp73 and amino-terminal truncated ΔNp73 to assess their effects on growth.

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Questioning the oncogenic role of ΔNp73α in different cell lines expressing p53 or not

Cited by 10 publications

References 27 publications

MCL1 binds and negatively regulates the transcriptional function of tumor suppressor p73

MCL1 binds and negatively regulates the transcriptional function of tumor suppressor p73

In vivo evaluation of the role of DNp73α protein in regulating the p53‐dependent apoptotic pathway after treatment with cytotoxic drugs

Overexpressed TP73 induces apoptosis in medulloblastoma

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