Nuclear interactor of ARF and Mdm2 regulates multiple pathways to activate p53

Reed, Sara M.; Hagen, Jussara; Tompkins, Van S.; Thies, Katie; Quelle, Frederick W.; Quelle, Dawn E.

doi:10.4161/cc.28202

Cited by 26 publications

(57 citation statements)

References 61 publications

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“…In addition, Mass Spectrometric (MS) analysis of a protein band (with the apparent size at ~14 kD molecular weight) revealed peptide sequences matching the ARF tumor suppressor (Figure 1A). ARF (known as p14ARF in human and p19ARF in mouse) was initially identified as the product of an alternative reading frame within the Ink4a/ARF tumor suppressor locus (Reed et al, 2014; Sherr, 2006; Wang et al, 2008). A major function of ARF is to activate the p53 pathway in response to oncogenic stress by inhibiting the enzymatic activity of certain ubiquitin E3 ligases (i.e., Mdm2 and ARF-BP1) that target p53 for proteasomal degradation (Forys et al, 2014; Reed et al, 2014; Sherr, 2006; Chen et al, 2005).…”

Section: Resultsmentioning

confidence: 99%

“…ARF (known as p14ARF in human and p19ARF in mouse) was initially identified as the product of an alternative reading frame within the Ink4a/ARF tumor suppressor locus (Reed et al, 2014; Sherr, 2006; Wang et al, 2008). A major function of ARF is to activate the p53 pathway in response to oncogenic stress by inhibiting the enzymatic activity of certain ubiquitin E3 ligases (i.e., Mdm2 and ARF-BP1) that target p53 for proteasomal degradation (Forys et al, 2014; Reed et al, 2014; Sherr, 2006; Chen et al, 2005). ARF can also act to suppress tumor growth in a p53-independent manner by the mechanisms that are not completely understood (Eischen and Boyd, 2012; Forys et al, 2014; Itahana and Zhang, 2008; Muniz et al, 2011).…”

Section: Resultsmentioning

confidence: 99%

“…Numerous studies indicate that ARF suppresses aberrant cell growth in response to oncogene activation by activating the p53 pathway. Although it is well established that ARF and p53 function in a linear pathway of tumor suppression (Reed et al, 2014;Sherr, 2006; Wang et al, 2008), accumulating evidence indicates that ARF also has p53-independent tumor-suppressor activities (Eischen et al, 2012; Forys et al, 2014; Itahana et al, 2008; Muniz et al, 2011). This notion is further supported by recent genomic analyses showing that ARF is inactivated in human cancers containing mutated p53 (Cancer Genome Atlas Research Network, 2012; O’Dell et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

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NRF2 Is a Major Target of ARF in p53-Independent Tumor Suppression

et al. 2017

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Summary Although ARF can suppress tumor growth by activating p53 function, the mechanisms by which it suppresses tumor growth independently of p53 are not well understood. Here, we identified ARF as a key regulator of nuclear factor-E2-related factor 2 (NRF2) through complex purification. ARF inhibits the ability of NRF2 to transcriptionally activate its target genes, including SLC7A11, a component of the cystine/glutamate antiporter that regulates reactive oxygen species (ROS)-induced ferroptosis. As a consequence, ARF expression sensitizes cells to ferroptosis in a p53-independent manner while ARF depletion induces NRF2 activation and promotes cancer cell survival in response to oxidative stress. Moreover, the ability of ARF to induce p53-independent tumor growth suppression in mouse xenograft models is significantly abrogated upon NRF2 overexpression. These results demonstrate that NRF2 is a major target of p53-independent tumor suppression by ARF and also suggest that the ARF-NRF2 interaction acts as a new checkpoint for oxidative stress responses.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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NRF2 Is a Major Target of ARF in p53-Independent Tumor Suppression

et al. 2017

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“…In humans, TIP60 is an essential player in different signaling pathways, including transcriptional regulation, chromatin remodeling, histone acetylation, and DNA repair . TIP60 acetylates the «-amino groups of Lys residues on both histone and nonhistone proteins, including diverse targets such as histone H2A and H4, p53, the ATAXIA-TELANGIECTASIA MUTATED (ATM) kinase, among others Reed et al, 2014). Different results suggest that TIP60 exerts diverse biological functions through mechanisms that are either dependent or independent of its intrinsic HAT activity, such as cellular signaling, DNA damage repair, cell cycle checkpoint control, and cell death induction .…”

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confidence: 99%

AtPDCD5 Plays a Role in Programmed Cell Death after UV-B Exposure in Arabidopsis

et al. 2016

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DNA damage responses have evolved to sense and react to DNA damage; the induction of DNA repair mechanisms can lead to genomic restoration or, if the damaged DNA cannot be adequately repaired, to the execution of a cell death program. In this work, we investigated the role of an Arabidopsis (Arabidopsis thaliana) protein, AtPDCD5, which is highly similar to the human PDCD5 protein; it is induced by ultraviolet (UV)-B radiation and participates in programmed cell death in the UV-B DNA damage response. Transgenic plants expressing AtPDCD5 fused to GREEN FLUORESCENT PROTEIN indicate that AtPDCD5 is localized both in the nucleus and the cytosol. By use of pdcd5 mutants, we here demonstrate that these plants have an altered antioxidant metabolism and accumulate higher levels of DNA damage after UV-B exposure, similar to levels in ham1ham2 RNA interference transgenic lines with decreased expression of acetyltransferases from the MYST family. By coimmunoprecipitation and pull-down assays, we provide evidence that AtPDCD5 interacts with HAM proteins, suggesting that both proteins participate in the same pathway of DNA damage responses. Plants overexpressing AtPDCD5 show less DNA damage but more cell death in root tips upon UV-B exposure. Finally, we here show that AtPDCD5 also participates in age-induced programmed cell death. Together, the data presented here demonstrate that AtPDCD5 plays an important role during DNA damage responses induced by UV-B radiation in Arabidopsis and also participates in programmed cell death programs.

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“…In the April 15, 2014 issue of Cell Cycle , Reed et al 2 investigated the pathways downstream of NIAM required for its growth-suppressive properties. What little was previously known about NIAM strongly suggested its ability to induce cell cycle arrest channels through multiple parallel pathways 3 .…”

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confidence: 99%