p14ARF Regulates E2F-1 Ubiquitination and Degradation via a p53-Dependent Mechanism

Rizos, Helen; Scurr, Lyndee L.; Irvine, Mal; Alling, Nikki; Kefford, Richard

doi:10.4161/cc.6.14.4428

Cited by 26 publications

(27 citation statements)

References 39 publications

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“…It has been reported that p53 is able to modulate degradation of certain proteins via either proteasomal 22 or lysosomal 23 pathway. Therefore, we next sought to determine whether the downregulation of EMMPRIN by p53 occured at protein level.…”

Section: Effects Of P53 Status On Emmprin Protein Expressionmentioning

confidence: 99%

A role for p53 in the regulation of extracellular matrix metalloproteinase inducer in human cancer cells

Zhu

Evans

O’Neill

et al. 2009

Cancer Biology & Therapy

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EMMPRIN, a transmembrane glycoprotein known to promote survival, invasion and metastasis of tumor cells through multiple pathways and mechanisms, has been found to be overexpressed in various types of cancer cells. Here we report that loss of the function of p53, a tumor suppressor protein that is mutated in approximately 50% of human cancers, contributes to the upregulation of EMMPRIN protein. We observed an inverse association between the activity of p53 and the level of EMMPRIN protein in several cancer cell lines. We further demonstrated that p53 is able to negatively regulate EMMPRIN protein, but downregulation of EMMPRIN by p53 is independent of repression of the EMMPRIN transcription. Furthermore, downregulation of EMMPRIN by p53 can be rescued by chloroquine, a lysosome inhibitor, but not by MG132, a proteasome inhibitor, suggesting an involvement of the lysosomal pathway in the p53-regulated degradation of EMMPRIN. Downregulation of EMMPRIN by p53 leads to a decrease in the activity of MMP-9 and an inhibition of tumor cell invasion. Our study suggests that the upregulation of EMMPRIN seen in many cancers can be attributed to, at least in part, the dysfunction of p53 and thus provides new evidence for the roles of p53 in tumor development and progression.

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Section: Effects Of P53 Status On Emmprin Protein Expressionmentioning

confidence: 99%

A role for p53 in the regulation of extracellular matrix metalloproteinase inducer in human cancer cells

Zhu

Evans

O’Neill

et al. 2009

Cancer Biology & Therapy

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“…Indeed, several p53-independent actions of ARF have recently been described (19), including antiviral response (7). Several reports have identified E2F1 as a potential mediator of ARF functions independently of p53 (20)(21)(22). Thus, ARF may target E2F1 for its degradation, thereby inhibiting E2F1-dependent transcription (20)(21)(22).…”

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confidence: 99%

“…Several reports have identified E2F1 as a potential mediator of ARF functions independently of p53 (20)(21)(22). Thus, ARF may target E2F1 for its degradation, thereby inhibiting E2F1-dependent transcription (20)(21)(22). The transcription factor E2F1 is one of the key proteins in the regulation of the G 1 /S phase transition, acting as a critical regulator of cell survival and proliferation (23).…”

mentioning

confidence: 99%

The Tumor Suppressor ARF Regulates Innate Immune Responses in Mice

Través

López-Fontal

Luque

et al. 2011

The Journal of Immunology

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The innate immune system is the first line of defense against invading organisms, and TLRs are the main sensors of microbial components, initiating signaling pathways that induce the production of proinflammatory cytokines and type I IFNs. An antiviral action for the tumor suppressor alternative reading frame (ARF) has been reported; however, the precise role of ARF in innate immunity is unknown. In this study, we show that ARF plays an important role in regulation of inflammatory responses. In peritoneal macrophages and bone marrow-derived macrophages from ARF-deficient animals, the induction of proinflammatory cytokines and chemokines by TLR ligands was severely impaired. The altered responses of ARF−/− cells to TLR ligands result from aberrant activation of intracellular signaling molecules including MAPKs, IκBα degradation, and NF-κB activation. Additionally, animals lacking ARF were resistant to LPS-induced endotoxic shock. This impaired activation of inflammation in ARF−/− mice was not restricted to TLRs, as it was also shown in response to non-TLR signaling pathways. Thus, ARF−/− mice were also unable to trigger a proper inflammatory response in experimental peritonitis or in 12-O-tetradecanoylphorbol-13-acetate–induced edema. Overexpression of ARF, but not its downstream target p53, rescued the ARF-deficient phenotype, increasing TLR4 levels and restoring inflammatory reaction. An increase in the E2F1 protein levels observed in ARF−/− macrophages at basal condition and after LPS stimulation may be involved in the impaired response in this system, as E2F1 has been described as an inflammatory suppressor. These results indicate that tumor suppressor ARF is a new regulator of inflammatory cell signaling.

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“…ARF inhibits the function of B23, a nucleolar endoribonuclease involved in 28 S RNA maturation, through promoting B23 polyubiquitination and proteasomal degradation (10). In some circumstances, overexpression of ARF destabilizes MDM2, E2F1, and DP1 by facilitating the polyubiquitination of the proteins (11)(12)(13)(14). Strikingly, in addition to promoting ubiquitin conjugation, ARF also targets a number of its binding partners including MDM2, NPM (B23), Werner helicase, HIF-1␣, and E2F1 for small ubiquitin-like modifier modification (11,15,16).…”

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confidence: 99%

Tumor Suppressor ARF Promotes Non-classic Proteasome-independent Polyubiquitination of COMMD1

Huang

2008

Journal of Biological Chemistry

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Although the tumor suppressor ARF is generally accepted for its essential role in activating the p53 pathway, its p53-independent function has also been proposed. Here, we report that ARF associates with COMMD1 and promotes Lys 63 -mediated polyubiquitination of COMMD1 in a p53-independent manner. We found that ARF interacts with COMMD1 in vivo. Deletion analysis of ARF suggested that the N-terminal amino acids 15-45 are important for its interaction with COMMD1. In addition, we found that endogenous ARF redistributes from the nucleolus to the nucleoplasm and interacts with COMMD1 when DNA is damaged by actinomycin D. Interestingly, we found that ARF promotes the polyubiquitination of COMMD1 through Lys 63 of ubiquitin but not the polyubiquitination of Lys 48 , which does not target COMMD1 for proteasome-dependent proteolysis. Moreover, ARF mutants lacking the domain interacting with COMMD1 did not promote COMMD1 polyubiquitination, indicating that physical association is a prerequisite condition for the polyubiquitination process. Together, these data suggest that the ability to promote Lys 63 -mediated polyubiquitination of COMMD1 is a novel property of ARF independent of p53.

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p14ARF Regulates E2F-1 Ubiquitination and Degradation via a p53-Dependent Mechanism

Cited by 26 publications

References 39 publications

A role for p53 in the regulation of extracellular matrix metalloproteinase inducer in human cancer cells

A role for p53 in the regulation of extracellular matrix metalloproteinase inducer in human cancer cells

The Tumor Suppressor ARF Regulates Innate Immune Responses in Mice

Tumor Suppressor ARF Promotes Non-classic Proteasome-independent Polyubiquitination of COMMD1

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