Dynamics of p14ARF and Focal Adhesion Kinase-Mediated Autophagy in Cancer

Fontana, Rosa; Vivo, Maria

doi:10.3390/cancers10070221

Cited by 9 publications

(6 citation statements)

References 109 publications

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“…As an important non-selective degradation machinery, autophagy is found to regulate the focal adhesion disassembly, β1 integrin membrane recycling, and the acquisition of mesenchymal markers, all of which are crucial for cell migration. While the precise positive or negative role for autophagy in cell migration varies depending on the cellular context (Tuloup-Minguez et al, 2013; Liu et al, 2017; Fontana and Vivo, 2018). To our knowledge, we firstly revealed the involvement of autophagy in the migration of keratinocyte under HG treatment.…”

Section: Discussionmentioning

confidence: 99%

High Glucose Suppresses Keratinocyte Migration Through the Inhibition of p38 MAPK/Autophagy Pathway

Zhang

et al. 2019

Front. Physiol.

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Wound healing is delayed frequently in patients with diabetes. Proper keratinocyte migration is an essential step during re-epithelialization. Impaired keratinocyte migration is a critical underlying factor responsible for the deficiency of diabetic wound healing, which is mainly attributed to the hyperglycemic state. However, the underlying mechanisms remain largely unknown. Previously, we demonstrated a marked activation of p38/mitogen-activated protein kinase (MAPK) pathway in the regenerated migrating epidermis, which in turn promoted keratinocyte migration. In the present study, we find that p38/MAPK pathway is downregulated and accompanied by inactivation of autophagy under high glucose (HG) environment. In addition, we demonstrate that inactivation of p38/MAPK and autophagy result in the inhibition of keratinocyte migration under HG environment, and the activating p38/MAPK by MKK6(Glu) overexpression rescues cell migration through an autophagy-dependent way. Moreover, diabetic wound epidermis shows a significant inhibition of p38/MAPK and autophagy. Targeting these dysfunctions may provide novel therapeutic approaches.

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Section: Discussionmentioning

confidence: 99%

High Glucose Suppresses Keratinocyte Migration Through the Inhibition of p38 MAPK/Autophagy Pathway

Zhang

et al. 2019

Front. Physiol.

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“…Although for several years ARF was considered to be dysfunctional when over-expressed in cancer tissues, surprisingly, ARF silencing was shown to limit the progression of Myc-driven lymphomas in mouse xenograft models [123]. In this study, Humbey and co-authors proposed for the first time that ARF can promote tumor progression through its ability to induce autophagy [60,124,125,126,127]. Autophagy is a lysosome-mediated process of self-digestion occurring during periods of nutrient deprivation.…”

Section: Arf Has Pro-oncogenic Functionsmentioning

confidence: 99%

“…Target proteins and organelles are enveloped by the autophagosome, a double-membrane vesicle, that fuses with the lysosome leading to the degradation of its contents. The released amino acids are thus recycled for the synthesis of essential proteins [124]. ARF silencing in Myc-driven lymphoma cells impaired autophagy and decreased the ability of these cells to form tumors in vivo.…”

Section: Arf Has Pro-oncogenic Functionsmentioning

confidence: 99%

“…Mitochondrial localized full-length ARF physically interacts with BCL-xL, a member of the Bcl2 family, that plays an important role in autophagy. The autophagy-inducing activity of ARF was shown to involve the displacement of Beclin-1 from BCL-xL complexes through direct binding of ARF to BCL-xL [124,154,155,156,157,158,159,160,161,162] thus promoting the activation of the key mediator of autophagy, the Beclin-1/Vps34 complex [124,154,155].…”

Section: Arf and Autophagymentioning

confidence: 99%

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Dual Role of the Alternative Reading Frame ARF Protein in Cancer

et al. 2019

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The CDKN2a/ARF locus expresses two partially overlapping transcripts that encode two distinct proteins, namely p14ARF (p19Arf in mouse) and p16INK4a, which present no sequence identity. Initial data obtained in mice showed that both proteins are potent tumor suppressors. In line with a tumor-suppressive role, ARF-deficient mice develop lymphomas, sarcomas, and adenocarcinomas, with a median survival rate of one year of age. In humans, the importance of ARF inactivation in cancer is less clear whereas a more obvious role has been documented for p16INK4a. Indeed, many alterations in human tumors result in the elimination of the entire locus, while the majority of point mutations affect p16INK4a. Nevertheless, specific mutations of p14ARF have been described in different types of human cancers such as colorectal and gastric carcinomas, melanoma and glioblastoma. The activity of the tumor suppressor ARF has been shown to rely on both p53-dependent and independent functions. However, novel data collected in the last years has challenged the traditional and established role of this protein as a tumor suppressor. In particular, tumors retaining ARF expression evolve to metastatic and invasive phenotypes and in humans are associated with a poor prognosis. In this review, the recent evidence and the molecular mechanisms of a novel role played by ARF will be presented and discussed, both in pathological and physiological contexts.

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“…So far it has been shown how p14ARF exerts a broader role in cell protection as, in addition to oncogenic stimuli, it can respond to a variety of different stresses arising in both pathological and physiological conditions, such as development, differentiation, aging and autophagy [ 6 , 7 , 8 , 9 ]. In particular, although since its discovery ARF was linked to anti-oncogenic functions, several experimental observations suggested for the first time that ARF can promote tumour progression [ 3 ].…”

Section: Introductionmentioning

confidence: 99%

Mutation of the Conserved Threonine 8 within the Human ARF Tumour Suppressor Protein Regulates Autophagy

et al. 2022

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Background: The ARF tumour suppressor plays a well-established role as a tumour suppressor, halting cell growth by both p53-dependent and independent pathways in several cellular stress response circuits. However, data collected in recent years challenged the traditional role of this protein as a tumour suppressor. Cancer cells expressing high ARF levels showed that its expression, far from being dispensable, is required to guarantee tumour cell survival. In particular, ARF can promote autophagy, a self-digestion pathway that helps cells cope with stressful growth conditions arising during both physiological and pathological processes. Methods: We previously showed that ARF is regulated through the activation of the protein kinase C (PKC)-dependent pathway and that an ARF phospho-mimetic mutant on the threonine residue 8, ARF-T8D, sustains cell proliferation in HeLa cells. We now explored the role of ARF phosphorylation in both basal and starvation-induced autophagy by analysing autophagic flux in cells transfected with either WT and ARF phosphorylation mutants by immunoblot and immunofluorescence. Results: Here, we show that endogenous ARF expression in HeLa cells is required for starvation-induced autophagy. Further, we provide evidence that the hyper-expression of ARF-T8D appears to inhibit autophagy in both HeLa and lung cancer cells H1299. This effect is due to the cells’ inability to elicit autophagosomes formation upon T8D expression. Conclusions: Our results lead to the hypothesis that ARF phosphorylation could be a mechanism through which the protein promotes or counteracts autophagy. Several observations underline how autophagy could serve a dual role in cancer progression, either protecting healthy cells from damage or aiding cancerous cells to survive. Our results indicate that ARF phosphorylation controls protein’s ability to promote or counteract autophagy, providing evidence of the dual role played by ARF in cancer progression.

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Dynamics of p14ARF and Focal Adhesion Kinase-Mediated Autophagy in Cancer

Cited by 9 publications

References 109 publications

High Glucose Suppresses Keratinocyte Migration Through the Inhibition of p38 MAPK/Autophagy Pathway

High Glucose Suppresses Keratinocyte Migration Through the Inhibition of p38 MAPK/Autophagy Pathway

Dual Role of the Alternative Reading Frame ARF Protein in Cancer

Mutation of the Conserved Threonine 8 within the Human ARF Tumour Suppressor Protein Regulates Autophagy

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