The Rac1/MKK7/JNK pathway signals upregulation of Atg5 and subsequent autophagic cell death in response to oncogenic Ras

Byun, Joo‐Yun; Yoon, Changhwan; An, Sungkwan; Park, In-Chul; Kang, Chang‐Mo; Kim, Minjung; Lee, Su‐Jae

doi:10.1093/carcin/bgp235

Cited by 120 publications

(93 citation statements)

References 36 publications

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“…3B). Although it is possible that autophagy is a secondary effect induced by the abnormal accumulation of intermediate filaments in our mutants, it has been reported that JNK signaling is directly involved in the formation of autophagic vacuoles and autophagic cell death (Byun et al, 2009;Shimizu et al, 2010;Kim et al, 2011;Xu et al, 2011). We are currently studying our Mkk7 flox/flox Nestin-Cre mice to determine whether MKK7-JNK signaling acts to suppress autophagy in the developing brain.…”

Section: Role Of Mkk7 In Neuronal Differentiationmentioning

confidence: 99%

Stress-Activated Protein Kinase MKK7 Regulates Axon Elongation in the Developing Cerebral Cortex

et al. 2011

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The c-Jun NH 2 -terminal protein kinase (JNK), which belongs to the mitogen-activated protein kinase family, plays important roles in a broad range of physiological processes. JNK is controlled by two upstream regulators, mitogen-activated protein kinase kinase (MKK) 7 and MKK4. To elucidate the physiological functions of MKK7, we used Nestin-Cre to generate a novel mouse model in which the mkk7 gene was specifically deleted in the nervous system (Mkk7 flox/flox Nestin-Cre mice). These mice were indistinguishable from their control littermates in gross appearance during embryogenesis but died immediately after birth without breathing. Histological examination showed that the mutants had severe defects in brain development, including enlarged ventricles, reduced striatum, and minimal axon tracts. Electron microscopy revealed abnormal accumulations of filamentous structures and autophagic vacuoles in Mkk7 flox/flox NestinCre brain. Further analysis showed that MKK7 deletion decreased numbers of TAG-1-expressing axons and delayed neuronal migration in the cerebrum. Neuronal differentiation was not altered. In utero electroporation studies showed that contralateral projection of axons by layer 2/3 neurons was impaired in the absence of MKK7. Moreover, MKK7 regulated axon elongation in a cell-autonomous manner in vivo, a finding confirmed in vitro. Finally, phosphorylation levels of JNK substrates, including c-Jun, neurofilament heavy chain, microtubule-associated protein 1B, and doublecortin, were reduced in Mkk7 flox/flox Nestin-Cre brain. Our findings demonstrate that the phenotype of Mkk7 flox/flox Nestin-Cre mice differs substantially from that of Mkk4 flox/flox Nestin-Cre mice, and establish that MKK7-mediated regulation of JNK is uniquely critical for both axon elongation and radial migration in the developing brain.

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Section: Role Of Mkk7 In Neuronal Differentiationmentioning

confidence: 99%

Stress-Activated Protein Kinase MKK7 Regulates Axon Elongation in the Developing Cerebral Cortex

et al. 2011

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“…When introduced into normal, untransformed cells, sustained activation of oncogenic HRas or KRas stimulate autophagy, which is then required for long-term cell survival and oncogenic transformation, presumably through the avoidance of cellular senescence 17 or the maintenance of a functional pool of mitochondria and additional bioenergetic effects 18,19 . However, acute transgene-enforced overexpression of oncogenic RAS can induce a cytotoxic level of autophagy, and depletion of several genes essential for autophagy, namely, Atg5, Atg7 or Beclin 1, avoid the demise of Ras-expressing cells 20,21 . Conversely, in established tumours, the Ras/PI3K/mammalian target of rapamycin signalling pathway may suppress autophagy, and inhibition of Ras then elicits cytoprotective autophagy 22 .…”

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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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“…RAS also inhibits autophagy by reducing Beclin-1 expression in intestinal epithelial cells, an important mediator of autophagy (10). However, RAS was reported to induce autophagy by increasing the expression of key components of the autophagy machinery, such as ATG5 (11) and Beclin-1 (12). These reports suggest that RAS signaling performs a finely regulated balancing act to control autophagy.…”

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confidence: 99%

Autophagic activity dictates the cellular response to oncogenic RAS

Wang

Lapi

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

107

124

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RAS is frequently mutated in human cancers and has opposing effects on autophagy and tumorigenesis. Identifying determinants of the cellular responses to RAS is therefore vital in cancer research. Here, we show that autophagic activity dictates the cellular response to oncogenic RAS. N-terminal Apoptosis-stimulating of p53 protein 2 (ASPP2) mediates RAS-induced senescence and inhibits autophagy. Oncogenic RAS-expressing ASPP2 (Δ3/Δ3) mouse embryonic fibroblasts that escape senescence express a high level of ATG5/ATG12. Consistent with the notion that autophagy levels control the cellular response to oncogenic RAS, overexpressing ATG5, but not autophagy-deficient ATG5 mutant K130R, bypasses RAS-induced senescence, whereas ATG5 or ATG3 deficiency predisposes to it. Mechanistically, ASPP2 inhibits RAS-induced autophagy by competing with ATG16 to bind ATG5/ATG12 and preventing ATG16/ATG5/ATG12 formation. Hence, ASPP2 modulates oncogenic RAS-induced autophagic activity to dictate the cellular response to RAS: to proliferate or senesce.A ctive mutations of RAS, one of the first oncogenes identified, occur in about 20% of human tumors (1). Oncogenic RAS can transform cells and promote tumorigenesis, although it can also induce senescence and suppress tumor growth (2). Senescent cells are arrested and incapable of responding to mitogens, although they are viable and metabolically active. Senescence is characterized by dramatic cellular remodelling, which is energetically demanding. Autophagy, a genetically regulated process responsible for the turnover of cellular proteins and damaged or superfluous organelles, is a stress response involved in energy homeostasis (3). It was shown that autophagy is a critical mediator of oncogenic RAS-induced senescence, suggesting a negative role of autophagy in tumorigenesis (4). In contrast, a number of recent studies showed that active RAS requires autophagy to maintain its oncogenic function in tumorigenesis, arguing for a positive role of autophagy in tumorigenesis (5-8). The underlying reason for the conflicting observations remains unclear.RAS activation inhibits autophagy by activating the PI3K/ AKT/mammalian target of rapamycin (mTOR) pathway (9), and rapamycin, an mTOR inhibitor, is a potent inducer of autophagy. RAS also inhibits autophagy by reducing Beclin-1 expression in intestinal epithelial cells, an important mediator of autophagy (10). However, RAS was reported to induce autophagy by increasing the expression of key components of the autophagy machinery, such as ATG5 (11) and Beclin-1 (12). These reports suggest that RAS signaling performs a finely regulated balancing act to control autophagy. Identification of switching molecules that determine the cellular responses to RAS is thus needed urgently.The tumor suppressor p53 is one of the most well-established pathways by which RAS mediates cellular senescence. A recent study also showed that p53 is able to regulate autophagic activity by inducing the expression of LC3 (13). However, it remains unknown whether the abilit...

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The Rac1/MKK7/JNK pathway signals upregulation of Atg5 and subsequent autophagic cell death in response to oncogenic Ras

Cited by 120 publications

References 36 publications

Stress-Activated Protein Kinase MKK7 Regulates Axon Elongation in the Developing Cerebral Cortex

Stress-Activated Protein Kinase MKK7 Regulates Axon Elongation in the Developing Cerebral Cortex

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

Autophagic activity dictates the cellular response to oncogenic RAS

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