Down-Regulation of Autophagy-Related Protein 5 (ATG5) Contributes to the Pathogenesis of Early-Stage Cutaneous Melanoma

He, Li; He, Zhaoyue; Rütte, Thomas von; Yousefi, Shída; Hunger, Robert E.; Simon, Hans‐Uwe

doi:10.1126/scitranslmed.3005864

Cited by 152 publications

(144 citation statements)

References 48 publications

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“…Autophagy is regulated by highly conserved autophagy-related proteins (ATGs) required for initiation of autophagosome formation, cargo collection and trafficking to the lysosomal compartment [78]. Autophagy-Related Protein 5 (ATG5), an E3 ubiquitin ligase required for autophagosome elongation, has recently been shown to be downregulated in melanomas compared to nevi and melanocytes [79]. This is accompanied by a general inhibition of autophagy.…”

Section: Lysosomes and Autophagosomes In Melanomasmentioning

confidence: 99%

“…This is accompanied by a general inhibition of autophagy. When ATG5 is ectopically expressed in melanoma cells, it is capable of inhibiting proliferation and inducing senescence, as well as increasing autophagy [79]. In this way, autophagy in general and ATG5 in particular function as tumor suppressors in melanoma [79].…”

Section: Lysosomes and Autophagosomes In Melanomasmentioning

confidence: 99%

“…When ATG5 is ectopically expressed in melanoma cells, it is capable of inhibiting proliferation and inducing senescence, as well as increasing autophagy [79]. In this way, autophagy in general and ATG5 in particular function as tumor suppressors in melanoma [79]. Interestingly, high MITF expression levels correlate with very low ATG5 and ATG7 levels in microarray expression data from a panel of 83 melanoma cell lines (appearing at positions 11,730 and 12,676, respectively, in Supplementary Table 1, p < 0.001).…”

Section: Lysosomes and Autophagosomes In Melanomasmentioning

confidence: 99%

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The MITF family of transcription factors: Role in endolysosomal biogenesis, Wnt signaling, and oncogenesis

Ploper

Robertis

2015

Pharmacological Research

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a b s t r a c tCanonical Wnt signaling influences cellular fate and proliferation through inhibition of Glycogen Synthase Kinase (GSK3) and the subsequent stabilization of its many substrates, most notably ␤-Catenin, a transcriptional co-activator. MITF, a melanoma oncogene member of the microphthalmia family of transcription factors (MiT), was recently found to contain novel GSK3 phosphorylation sites and to be stabilized by Wnt. Other MiT members, TFEB and TFE3, are known to play important roles in cellular clearance pathways by transcriptionally regulating the biogenesis of lysosomes and autophagosomes via activation of CLEAR elements in gene promoters of target genes. Recent studies suggest that MITF can also upregulate many lysosomal genes. MiT family members are dysregulated in cancer and are considered oncogenes, but the underlying oncogenic mechanisms remain unclear. Here we review the role of MiT members, including MITF, in lysosomal biogenesis, and how cancers overexpressing MITF, TFEB or TFE3 could rewire the lysosomal pathway, inhibit cellular senescence, and activate Wnt signaling by increasing sequestration of negative regulators of Wnt signaling in multivesicular bodies (MVBs). Microarray studies suggest that MITF expression inhibits macroautophagy. In melanoma the MITF-driven increase in MVBs generates a positive feedback loop between MITF, Wnt, and MVBs.

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Section: Lysosomes and Autophagosomes In Melanomasmentioning

confidence: 99%

Section: Lysosomes and Autophagosomes In Melanomasmentioning

confidence: 99%

Section: Lysosomes and Autophagosomes In Melanomasmentioning

confidence: 99%

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The MITF family of transcription factors: Role in endolysosomal biogenesis, Wnt signaling, and oncogenesis

Ploper

Robertis

2015

Pharmacological Research

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“…Furthermore, since EI24/ PIG8 is also known as the proapoptotic factor [84,85], this role may contribute to tumor suppression. Besides Beclin 1 and EI24, altered expression of several autophagy proteins such as ATG5 [86,87], and UVRAG [88] are www.cell-research.com | Cell Research Peidu Jiang and Noboru Mizushima 73 npg reported to be associated with human cancers [7,89].…”

Section: Cancermentioning

confidence: 99%

Autophagy and human diseases

2013

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Autophagy is a major intracellular degradative process that delivers cytoplasmic materials to the lysosome for degradation. Since the discovery of autophagy-related (Atg) genes in the 1990s, there has been a proliferation of studies on the physiological and pathological roles of autophagy in a variety of autophagy knockout models. However, direct evidence of the connections between ATG gene dysfunction and human diseases has emerged only recently. There are an increasing number of reports showing that mutations in the ATG genes were identified in various human diseases such as neurodegenerative diseases, infectious diseases, and cancers. Here, we review the major advances in identification of mutations or polymorphisms of the ATG genes in human diseases. Current autophagy-modulating compounds in clinical trials are also summarized.

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“…4). We deliberately chose to regulate autophagy by modulating Atg5 expression because this gene is essential for the initiation of autophagy 4,24 and its expression levels correlate with autophagy in human tumours 25,26 . Here we report the systematic comparison of autophagy-competent (Atg5-expressing) and autophagy-deficient (Atg5-deleted) KRas G12D lung cancers.…”

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confidence: 99%

A dual role for autophagy in a murine model of lung cancer

et al. 2014

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Autophagy is a mechanism by which starving cells can control their energy requirements and metabolic states, thus facilitating the survival of cells in stressful environments, in particular in the pathogenesis of cancer. Here we report that tissue-specific inactivation of Atg5, essential for the formation of autophagosomes, markedly impairs the progression of KRas G12D -driven lung cancer, resulting in a significant survival advantage of tumour-bearing mice. Autophagydefective lung cancers exhibit impaired mitochondrial energy homoeostasis, oxidative stress and a constitutively active DNA damage response. Genetic deletion of the tumour suppressor p53 reinstates cancer progression of autophagy-deficient tumours. Although there is improved survival, the onset of Atg5-mutant KRas G12D -driven lung tumours is markedly accelerated. Mechanistically, increased oncogenesis maps to regulatory T cells. These results demonstrate that, in KRas G12D -driven lung cancer, Atg5-regulated autophagy accelerates tumour progression; however, autophagy also represses early oncogenesis, suggesting a link between deregulated autophagy and regulatory T cell controlled anticancer immunity.

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Down-Regulation of Autophagy-Related Protein 5 (ATG5) Contributes to the Pathogenesis of Early-Stage Cutaneous Melanoma

Cited by 152 publications

References 48 publications

The MITF family of transcription factors: Role in endolysosomal biogenesis, Wnt signaling, and oncogenesis

The MITF family of transcription factors: Role in endolysosomal biogenesis, Wnt signaling, and oncogenesis

Autophagy and human diseases

A dual role for autophagy in a murine model of lung cancer

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