NEDD4L downregulates autophagy and cell growth by modulating ULK1 and a glutamine transporter
Identifieur interne : 000E52 ( Ncbi/Curation ); précédent : 000E51; suivant : 000E53NEDD4L downregulates autophagy and cell growth by modulating ULK1 and a glutamine transporter
Auteurs : Dong-Eun Lee ; Ju Eun Yoo ; Jiyea Kim ; Seungki Kim ; Sunshin Kim ; Ho Lee ; Heesun CheongSource :
- Cell Death & Disease [ 2041-4889 ] ; 2020.
Abstract
In mammals, autophagosome formation is initiated by ULK1 via the posttranslational modification of this protein. However, the precise role of ULK1 ubiquitination in modulating autophagy is unknown. Here, we show that NEDD4L, an E3 ubiquitin ligase, binds ULK1 in pancreatic cancer cells. ULK1 expression was stabilized in NEDD4L knockdown cells compared to that in control cells, suggesting that NEDD4L is involved in ULK1 ubiquitination and its subsequent degradation. Autophagy activity was enhanced in NEDD4L knockdown cells compared to control cells. NEDD4L-depleted cells exhibited an increase in the cellular oxygen consumption rate (OCR) and mitochondrial membrane potential, and maintained mitochondrial fusion status in response to metabolic stress. Enhanced OCR and mitochondrial fusion morphology in NEDD4L knockdown cells were repressed by siRNA targeting ULK1. In addition to ULK1, ASCT2, a glutamine transporter, was accumulated in NEDD4L-depleted cells; this is important for maintaining autophagy activation and mitochondrial metabolic function. Finally, the cellular growth and survival rate increased in NEDD4L knockdown cells compared to control cells. However, the genetic or pharmacological blockade of either ULK1 or ASCT2 in NEDD4L-depleted cells sensitized pancreatic cancer cells, particularly in response to nutrient deprivation. In a mouse xenograft model of pancreatic cancer, the use of autophagy inhibitors suppressed tumor growth more in NEDD4L-depleted cells than in tumors from control cells. NEDD4L and ULK1 levels were inversely correlated in two different pancreatic cancer mouse models-xenograft mouse and KPC mouse models. These results suggest that NEDD4L suppressed autophagy and mitochondrial metabolism by reducing cellular ULK1 or ASCT2 levels, and thus could repress the growth and survival of pancreatic cancer cells. Therefore, ubiquitin ligase-mediated autophagy plays a critical role in regulating mitochondrial metabolism, thereby contributing to the growth and survival of certain cancers with low NEDD4L levels.
Url:
DOI: 10.1038/s41419-020-2242-5
PubMed: 31959741
PubMed Central: 6971022
Links toward previous steps (curation, corpus...)
- to stream Pmc, to step Corpus: Pour aller vers cette notice dans l'étape Curation :000078
- to stream Pmc, to step Curation: Pour aller vers cette notice dans l'étape Curation :000078
- to stream Pmc, to step Checkpoint: Pour aller vers cette notice dans l'étape Curation :000092
- to stream Ncbi, to step Merge: Pour aller vers cette notice dans l'étape Curation :000E52
Links to Exploration step
PMC:6971022Curation
No country items
Dong-Eun Lee<affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0628 9810</institution-id>
<institution-id institution-id-type="GRID">grid.410914.9</institution-id>
<institution>Research Institute, National Cancer Center, 323 Ilsan-Ro, Ilsandong-Gu,</institution>
</institution-wrap>
Goyang-Si, Gyeonggi-Do Republic of Korea</nlm:aff>
<wicri:noCountry code="subfield">Gyeonggi-Do Republic of Korea</wicri:noCountry>
</affiliation>
<affiliation><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0628 9810</institution-id>
<institution-id institution-id-type="GRID">grid.410914.9</institution-id>
<institution>Department of Cancer Biomedical Science,</institution>
<institution>Graduate School of Cancer Science & Policy, National Cancer Center, 323 Ilsan-Ro, Ilsandong-Gu,</institution>
</institution-wrap>
Goyang-Si, Gyeonggi-Do Republic of Korea</nlm:aff>
<wicri:noCountry code="subfield">Gyeonggi-Do Republic of Korea</wicri:noCountry>
</affiliation>
<affiliation><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0628 9810</institution-id>
<institution-id institution-id-type="GRID">grid.410914.9</institution-id>
<institution>Department of Cancer Biomedical Science,</institution>
<institution>Graduate School of Cancer Science & Policy, National Cancer Center, 323 Ilsan-Ro, Ilsandong-Gu,</institution>
</institution-wrap>
Goyang-Si, Gyeonggi-Do Republic of Korea</nlm:aff>
<wicri:noCountry code="subfield">Gyeonggi-Do Republic of Korea</wicri:noCountry>
</affiliation>
<affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0628 9810</institution-id>
<institution-id institution-id-type="GRID">grid.410914.9</institution-id>
<institution>Research Institute, National Cancer Center, 323 Ilsan-Ro, Ilsandong-Gu,</institution>
</institution-wrap>
Goyang-Si, Gyeonggi-Do Republic of Korea</nlm:aff>
<wicri:noCountry code="subfield">Gyeonggi-Do Republic of Korea</wicri:noCountry>
</affiliation>
<affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0628 9810</institution-id>
<institution-id institution-id-type="GRID">grid.410914.9</institution-id>
<institution>Research Institute, National Cancer Center, 323 Ilsan-Ro, Ilsandong-Gu,</institution>
</institution-wrap>
Goyang-Si, Gyeonggi-Do Republic of Korea</nlm:aff>
<wicri:noCountry code="subfield">Gyeonggi-Do Republic of Korea</wicri:noCountry>
</affiliation>
<affiliation><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0628 9810</institution-id>
<institution-id institution-id-type="GRID">grid.410914.9</institution-id>
<institution>Department of Cancer Biomedical Science,</institution>
<institution>Graduate School of Cancer Science & Policy, National Cancer Center, 323 Ilsan-Ro, Ilsandong-Gu,</institution>
</institution-wrap>
Goyang-Si, Gyeonggi-Do Republic of Korea</nlm:aff>
<wicri:noCountry code="subfield">Gyeonggi-Do Republic of Korea</wicri:noCountry>
</affiliation>
<affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0628 9810</institution-id>
<institution-id institution-id-type="GRID">grid.410914.9</institution-id>
<institution>Research Institute, National Cancer Center, 323 Ilsan-Ro, Ilsandong-Gu,</institution>
</institution-wrap>
Goyang-Si, Gyeonggi-Do Republic of Korea</nlm:aff>
<wicri:noCountry code="subfield">Gyeonggi-Do Republic of Korea</wicri:noCountry>
</affiliation>
<affiliation><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0628 9810</institution-id>
<institution-id institution-id-type="GRID">grid.410914.9</institution-id>
<institution>Department of Cancer Biomedical Science,</institution>
<institution>Graduate School of Cancer Science & Policy, National Cancer Center, 323 Ilsan-Ro, Ilsandong-Gu,</institution>
</institution-wrap>
Goyang-Si, Gyeonggi-Do Republic of Korea</nlm:aff>
<wicri:noCountry code="subfield">Gyeonggi-Do Republic of Korea</wicri:noCountry>
</affiliation>
<affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0628 9810</institution-id>
<institution-id institution-id-type="GRID">grid.410914.9</institution-id>
<institution>Research Institute, National Cancer Center, 323 Ilsan-Ro, Ilsandong-Gu,</institution>
</institution-wrap>
Goyang-Si, Gyeonggi-Do Republic of Korea</nlm:aff>
<wicri:noCountry code="subfield">Gyeonggi-Do Republic of Korea</wicri:noCountry>
</affiliation>
<affiliation><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0628 9810</institution-id>
<institution-id institution-id-type="GRID">grid.410914.9</institution-id>
<institution>Department of Cancer Biomedical Science,</institution>
<institution>Graduate School of Cancer Science & Policy, National Cancer Center, 323 Ilsan-Ro, Ilsandong-Gu,</institution>
</institution-wrap>
Goyang-Si, Gyeonggi-Do Republic of Korea</nlm:aff>
<wicri:noCountry code="subfield">Gyeonggi-Do Republic of Korea</wicri:noCountry>
</affiliation>
<affiliation><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0628 9810</institution-id>
<institution-id institution-id-type="GRID">grid.410914.9</institution-id>
<institution>Department of Cancer Biomedical Science,</institution>
<institution>Graduate School of Cancer Science & Policy, National Cancer Center, 323 Ilsan-Ro, Ilsandong-Gu,</institution>
</institution-wrap>
Goyang-Si, Gyeonggi-Do Republic of Korea</nlm:aff>
<wicri:noCountry code="subfield">Gyeonggi-Do Republic of Korea</wicri:noCountry>
</affiliation>
Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">NEDD4L downregulates autophagy and cell growth by modulating ULK1 and a glutamine transporter</title>
<author><name sortKey="Lee, Dong Eun" sort="Lee, Dong Eun" uniqKey="Lee D" first="Dong-Eun" last="Lee">Dong-Eun Lee</name>
<affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0628 9810</institution-id>
<institution-id institution-id-type="GRID">grid.410914.9</institution-id>
<institution>Research Institute, National Cancer Center, 323 Ilsan-Ro, Ilsandong-Gu,</institution>
</institution-wrap>
Goyang-Si, Gyeonggi-Do Republic of Korea</nlm:aff>
<wicri:noCountry code="subfield">Gyeonggi-Do Republic of Korea</wicri:noCountry>
</affiliation>
<affiliation><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0628 9810</institution-id>
<institution-id institution-id-type="GRID">grid.410914.9</institution-id>
<institution>Department of Cancer Biomedical Science,</institution>
<institution>Graduate School of Cancer Science & Policy, National Cancer Center, 323 Ilsan-Ro, Ilsandong-Gu,</institution>
</institution-wrap>
Goyang-Si, Gyeonggi-Do Republic of Korea</nlm:aff>
<wicri:noCountry code="subfield">Gyeonggi-Do Republic of Korea</wicri:noCountry>
</affiliation>
</author>
<author><name sortKey="Yoo, Ju Eun" sort="Yoo, Ju Eun" uniqKey="Yoo J" first="Ju Eun" last="Yoo">Ju Eun Yoo</name>
<affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0628 9810</institution-id>
<institution-id institution-id-type="GRID">grid.410914.9</institution-id>
<institution>Research Institute, National Cancer Center, 323 Ilsan-Ro, Ilsandong-Gu,</institution>
</institution-wrap>
Goyang-Si, Gyeonggi-Do Republic of Korea</nlm:aff>
<wicri:noCountry code="subfield">Gyeonggi-Do Republic of Korea</wicri:noCountry>
</affiliation>
</author>
<author><name sortKey="Kim, Jiyea" sort="Kim, Jiyea" uniqKey="Kim J" first="Jiyea" last="Kim">Jiyea Kim</name>
<affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0628 9810</institution-id>
<institution-id institution-id-type="GRID">grid.410914.9</institution-id>
<institution>Research Institute, National Cancer Center, 323 Ilsan-Ro, Ilsandong-Gu,</institution>
</institution-wrap>
Goyang-Si, Gyeonggi-Do Republic of Korea</nlm:aff>
<wicri:noCountry code="subfield">Gyeonggi-Do Republic of Korea</wicri:noCountry>
</affiliation>
</author>
<author><name sortKey="Kim, Seungki" sort="Kim, Seungki" uniqKey="Kim S" first="Seungki" last="Kim">Seungki Kim</name>
<affiliation><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0628 9810</institution-id>
<institution-id institution-id-type="GRID">grid.410914.9</institution-id>
<institution>Department of Cancer Biomedical Science,</institution>
<institution>Graduate School of Cancer Science & Policy, National Cancer Center, 323 Ilsan-Ro, Ilsandong-Gu,</institution>
</institution-wrap>
Goyang-Si, Gyeonggi-Do Republic of Korea</nlm:aff>
<wicri:noCountry code="subfield">Gyeonggi-Do Republic of Korea</wicri:noCountry>
</affiliation>
</author>
<author><name sortKey="Kim, Sunshin" sort="Kim, Sunshin" uniqKey="Kim S" first="Sunshin" last="Kim">Sunshin Kim</name>
<affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0628 9810</institution-id>
<institution-id institution-id-type="GRID">grid.410914.9</institution-id>
<institution>Research Institute, National Cancer Center, 323 Ilsan-Ro, Ilsandong-Gu,</institution>
</institution-wrap>
Goyang-Si, Gyeonggi-Do Republic of Korea</nlm:aff>
<wicri:noCountry code="subfield">Gyeonggi-Do Republic of Korea</wicri:noCountry>
</affiliation>
</author>
<author><name sortKey="Lee, Ho" sort="Lee, Ho" uniqKey="Lee H" first="Ho" last="Lee">Ho Lee</name>
<affiliation><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0628 9810</institution-id>
<institution-id institution-id-type="GRID">grid.410914.9</institution-id>
<institution>Department of Cancer Biomedical Science,</institution>
<institution>Graduate School of Cancer Science & Policy, National Cancer Center, 323 Ilsan-Ro, Ilsandong-Gu,</institution>
</institution-wrap>
Goyang-Si, Gyeonggi-Do Republic of Korea</nlm:aff>
<wicri:noCountry code="subfield">Gyeonggi-Do Republic of Korea</wicri:noCountry>
</affiliation>
</author>
<author><name sortKey="Cheong, Heesun" sort="Cheong, Heesun" uniqKey="Cheong H" first="Heesun" last="Cheong">Heesun Cheong</name>
<affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0628 9810</institution-id>
<institution-id institution-id-type="GRID">grid.410914.9</institution-id>
<institution>Research Institute, National Cancer Center, 323 Ilsan-Ro, Ilsandong-Gu,</institution>
</institution-wrap>
Goyang-Si, Gyeonggi-Do Republic of Korea</nlm:aff>
<wicri:noCountry code="subfield">Gyeonggi-Do Republic of Korea</wicri:noCountry>
</affiliation>
<affiliation><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0628 9810</institution-id>
<institution-id institution-id-type="GRID">grid.410914.9</institution-id>
<institution>Department of Cancer Biomedical Science,</institution>
<institution>Graduate School of Cancer Science & Policy, National Cancer Center, 323 Ilsan-Ro, Ilsandong-Gu,</institution>
</institution-wrap>
Goyang-Si, Gyeonggi-Do Republic of Korea</nlm:aff>
<wicri:noCountry code="subfield">Gyeonggi-Do Republic of Korea</wicri:noCountry>
</affiliation>
</author>
</titleStmt>
<publicationStmt><idno type="wicri:source">PMC</idno>
<idno type="pmid">31959741</idno>
<idno type="pmc">6971022</idno>
<idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6971022</idno>
<idno type="RBID">PMC:6971022</idno>
<idno type="doi">10.1038/s41419-020-2242-5</idno>
<date when="2020">2020</date>
<idno type="wicri:Area/Pmc/Corpus">000078</idno>
<idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000078</idno>
<idno type="wicri:Area/Pmc/Curation">000078</idno>
<idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">000078</idno>
<idno type="wicri:Area/Pmc/Checkpoint">000092</idno>
<idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Checkpoint">000092</idno>
<idno type="wicri:Area/Ncbi/Merge">000E52</idno>
<idno type="wicri:Area/Ncbi/Curation">000E52</idno>
</publicationStmt>
<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">NEDD4L downregulates autophagy and cell growth by modulating ULK1 and a glutamine transporter</title>
<author><name sortKey="Lee, Dong Eun" sort="Lee, Dong Eun" uniqKey="Lee D" first="Dong-Eun" last="Lee">Dong-Eun Lee</name>
<affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0628 9810</institution-id>
<institution-id institution-id-type="GRID">grid.410914.9</institution-id>
<institution>Research Institute, National Cancer Center, 323 Ilsan-Ro, Ilsandong-Gu,</institution>
</institution-wrap>
Goyang-Si, Gyeonggi-Do Republic of Korea</nlm:aff>
<wicri:noCountry code="subfield">Gyeonggi-Do Republic of Korea</wicri:noCountry>
</affiliation>
<affiliation><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0628 9810</institution-id>
<institution-id institution-id-type="GRID">grid.410914.9</institution-id>
<institution>Department of Cancer Biomedical Science,</institution>
<institution>Graduate School of Cancer Science & Policy, National Cancer Center, 323 Ilsan-Ro, Ilsandong-Gu,</institution>
</institution-wrap>
Goyang-Si, Gyeonggi-Do Republic of Korea</nlm:aff>
<wicri:noCountry code="subfield">Gyeonggi-Do Republic of Korea</wicri:noCountry>
</affiliation>
</author>
<author><name sortKey="Yoo, Ju Eun" sort="Yoo, Ju Eun" uniqKey="Yoo J" first="Ju Eun" last="Yoo">Ju Eun Yoo</name>
<affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0628 9810</institution-id>
<institution-id institution-id-type="GRID">grid.410914.9</institution-id>
<institution>Research Institute, National Cancer Center, 323 Ilsan-Ro, Ilsandong-Gu,</institution>
</institution-wrap>
Goyang-Si, Gyeonggi-Do Republic of Korea</nlm:aff>
<wicri:noCountry code="subfield">Gyeonggi-Do Republic of Korea</wicri:noCountry>
</affiliation>
</author>
<author><name sortKey="Kim, Jiyea" sort="Kim, Jiyea" uniqKey="Kim J" first="Jiyea" last="Kim">Jiyea Kim</name>
<affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0628 9810</institution-id>
<institution-id institution-id-type="GRID">grid.410914.9</institution-id>
<institution>Research Institute, National Cancer Center, 323 Ilsan-Ro, Ilsandong-Gu,</institution>
</institution-wrap>
Goyang-Si, Gyeonggi-Do Republic of Korea</nlm:aff>
<wicri:noCountry code="subfield">Gyeonggi-Do Republic of Korea</wicri:noCountry>
</affiliation>
</author>
<author><name sortKey="Kim, Seungki" sort="Kim, Seungki" uniqKey="Kim S" first="Seungki" last="Kim">Seungki Kim</name>
<affiliation><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0628 9810</institution-id>
<institution-id institution-id-type="GRID">grid.410914.9</institution-id>
<institution>Department of Cancer Biomedical Science,</institution>
<institution>Graduate School of Cancer Science & Policy, National Cancer Center, 323 Ilsan-Ro, Ilsandong-Gu,</institution>
</institution-wrap>
Goyang-Si, Gyeonggi-Do Republic of Korea</nlm:aff>
<wicri:noCountry code="subfield">Gyeonggi-Do Republic of Korea</wicri:noCountry>
</affiliation>
</author>
<author><name sortKey="Kim, Sunshin" sort="Kim, Sunshin" uniqKey="Kim S" first="Sunshin" last="Kim">Sunshin Kim</name>
<affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0628 9810</institution-id>
<institution-id institution-id-type="GRID">grid.410914.9</institution-id>
<institution>Research Institute, National Cancer Center, 323 Ilsan-Ro, Ilsandong-Gu,</institution>
</institution-wrap>
Goyang-Si, Gyeonggi-Do Republic of Korea</nlm:aff>
<wicri:noCountry code="subfield">Gyeonggi-Do Republic of Korea</wicri:noCountry>
</affiliation>
</author>
<author><name sortKey="Lee, Ho" sort="Lee, Ho" uniqKey="Lee H" first="Ho" last="Lee">Ho Lee</name>
<affiliation><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0628 9810</institution-id>
<institution-id institution-id-type="GRID">grid.410914.9</institution-id>
<institution>Department of Cancer Biomedical Science,</institution>
<institution>Graduate School of Cancer Science & Policy, National Cancer Center, 323 Ilsan-Ro, Ilsandong-Gu,</institution>
</institution-wrap>
Goyang-Si, Gyeonggi-Do Republic of Korea</nlm:aff>
<wicri:noCountry code="subfield">Gyeonggi-Do Republic of Korea</wicri:noCountry>
</affiliation>
</author>
<author><name sortKey="Cheong, Heesun" sort="Cheong, Heesun" uniqKey="Cheong H" first="Heesun" last="Cheong">Heesun Cheong</name>
<affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0628 9810</institution-id>
<institution-id institution-id-type="GRID">grid.410914.9</institution-id>
<institution>Research Institute, National Cancer Center, 323 Ilsan-Ro, Ilsandong-Gu,</institution>
</institution-wrap>
Goyang-Si, Gyeonggi-Do Republic of Korea</nlm:aff>
<wicri:noCountry code="subfield">Gyeonggi-Do Republic of Korea</wicri:noCountry>
</affiliation>
<affiliation><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0628 9810</institution-id>
<institution-id institution-id-type="GRID">grid.410914.9</institution-id>
<institution>Department of Cancer Biomedical Science,</institution>
<institution>Graduate School of Cancer Science & Policy, National Cancer Center, 323 Ilsan-Ro, Ilsandong-Gu,</institution>
</institution-wrap>
Goyang-Si, Gyeonggi-Do Republic of Korea</nlm:aff>
<wicri:noCountry code="subfield">Gyeonggi-Do Republic of Korea</wicri:noCountry>
</affiliation>
</author>
</analytic>
<series><title level="j">Cell Death & Disease</title>
<idno type="eISSN">2041-4889</idno>
<imprint><date when="2020">2020</date>
</imprint>
</series>
</biblStruct>
</sourceDesc>
</fileDesc>
<profileDesc><textClass></textClass>
</profileDesc>
</teiHeader>
<front><div type="abstract" xml:lang="en"><p id="Par1">In mammals, autophagosome formation is initiated by ULK1 via the posttranslational modification of this protein. However, the precise role of ULK1 ubiquitination in modulating autophagy is unknown. Here, we show that NEDD4L, an E3 ubiquitin ligase, binds ULK1 in pancreatic cancer cells. ULK1 expression was stabilized in NEDD4L knockdown cells compared to that in control cells, suggesting that NEDD4L is involved in ULK1 ubiquitination and its subsequent degradation. Autophagy activity was enhanced in NEDD4L knockdown cells compared to control cells. NEDD4L-depleted cells exhibited an increase in the cellular oxygen consumption rate (OCR) and mitochondrial membrane potential, and maintained mitochondrial fusion status in response to metabolic stress. Enhanced OCR and mitochondrial fusion morphology in NEDD4L knockdown cells were repressed by siRNA targeting ULK1. In addition to ULK1, ASCT2, a glutamine transporter, was accumulated in NEDD4L-depleted cells; this is important for maintaining autophagy activation and mitochondrial metabolic function. Finally, the cellular growth and survival rate increased in NEDD4L knockdown cells compared to control cells. However, the genetic or pharmacological blockade of either ULK1 or ASCT2 in NEDD4L-depleted cells sensitized pancreatic cancer cells, particularly in response to nutrient deprivation. In a mouse xenograft model of pancreatic cancer, the use of autophagy inhibitors suppressed tumor growth more in NEDD4L-depleted cells than in tumors from control cells. NEDD4L and ULK1 levels were inversely correlated in two different pancreatic cancer mouse models-xenograft mouse and KPC mouse models. These results suggest that NEDD4L suppressed autophagy and mitochondrial metabolism by reducing cellular ULK1 or ASCT2 levels, and thus could repress the growth and survival of pancreatic cancer cells. Therefore, ubiquitin ligase-mediated autophagy plays a critical role in regulating mitochondrial metabolism, thereby contributing to the growth and survival of certain cancers with low NEDD4L levels.</p>
</div>
</front>
<back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Feng, Y" uniqKey="Feng Y">Y Feng</name>
</author>
<author><name sortKey="He, D" uniqKey="He D">D He</name>
</author>
<author><name sortKey="Yao, Z" uniqKey="Yao Z">Z Yao</name>
</author>
<author><name sortKey="Klionsky, Dj" uniqKey="Klionsky D">DJ Klionsky</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="He, C" uniqKey="He C">C He</name>
</author>
<author><name sortKey="Klionsky, Dj" uniqKey="Klionsky D">DJ Klionsky</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Kimmelman, Ac" uniqKey="Kimmelman A">AC Kimmelman</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Cheong, H" uniqKey="Cheong H">H Cheong</name>
</author>
<author><name sortKey="Lu, C" uniqKey="Lu C">C Lu</name>
</author>
<author><name sortKey="Lindsten, T" uniqKey="Lindsten T">T Lindsten</name>
</author>
<author><name sortKey="Thompson, Cb" uniqKey="Thompson C">CB Thompson</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Jiang, P" uniqKey="Jiang P">P Jiang</name>
</author>
<author><name sortKey="Mizushima, N" uniqKey="Mizushima N">N Mizushima</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Choi, Am" uniqKey="Choi A">AM Choi</name>
</author>
<author><name sortKey="Ryter, Sw" uniqKey="Ryter S">SW Ryter</name>
</author>
<author><name sortKey="Levine, B" uniqKey="Levine B">B Levine</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Jiang, X" uniqKey="Jiang X">X Jiang</name>
</author>
<author><name sortKey="Overholtzer, M" uniqKey="Overholtzer M">M Overholtzer</name>
</author>
<author><name sortKey="Thompson, Cb" uniqKey="Thompson C">CB Thompson</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Noda, Nn" uniqKey="Noda N">NN Noda</name>
</author>
<author><name sortKey="Fujioka, Y" uniqKey="Fujioka Y">Y Fujioka</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Egan, Df" uniqKey="Egan D">DF Egan</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Kuang, E" uniqKey="Kuang E">E Kuang</name>
</author>
<author><name sortKey="Qi, J" uniqKey="Qi J">J Qi</name>
</author>
<author><name sortKey="Ronai, Z" uniqKey="Ronai Z">Z Ronai</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Nazio, F" uniqKey="Nazio F">F Nazio</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Efeyan, A" uniqKey="Efeyan A">A Efeyan</name>
</author>
<author><name sortKey="Comb, Wc" uniqKey="Comb W">WC Comb</name>
</author>
<author><name sortKey="Sabatini, Dm" uniqKey="Sabatini D">DM Sabatini</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Liu, Cc" uniqKey="Liu C">CC Liu</name>
</author>
</analytic>
</biblStruct>
<biblStruct></biblStruct>
<biblStruct></biblStruct>
<biblStruct><analytic><author><name sortKey="Goel, P" uniqKey="Goel P">P Goel</name>
</author>
<author><name sortKey="Manning, Ja" uniqKey="Manning J">JA Manning</name>
</author>
<author><name sortKey="Kumar, S" uniqKey="Kumar S">S Kumar</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Dieter, M" uniqKey="Dieter M">M Dieter</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Ding, Yi" uniqKey="Ding Y">Yi Ding</name>
</author>
<author><name sortKey="Zhang, Yan" uniqKey="Zhang Y">Yan Zhang</name>
</author>
<author><name sortKey="Xu, Chao" uniqKey="Xu C">Chao Xu</name>
</author>
<author><name sortKey="Tao, Qing Hua" uniqKey="Tao Q">Qing-Hua Tao</name>
</author>
<author><name sortKey="Chen, Ye Guang" uniqKey="Chen Y">Ye-Guang Chen</name>
</author>
</analytic>
</biblStruct>
<biblStruct></biblStruct>
<biblStruct><analytic><author><name sortKey="Kuratomi, G" uniqKey="Kuratomi G">G Kuratomi</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Gao, S" uniqKey="Gao S">S Gao</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Nazio, F" uniqKey="Nazio F">F Nazio</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Gao, C" uniqKey="Gao C">C Gao</name>
</author>
<author><name sortKey="Pang, L" uniqKey="Pang L">L Pang</name>
</author>
<author><name sortKey="Ren, C" uniqKey="Ren C">C Ren</name>
</author>
<author><name sortKey="Ma, T" uniqKey="Ma T">T Ma</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Sakashita, H" uniqKey="Sakashita H">H Sakashita</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Tanksley, Jp" uniqKey="Tanksley J">JP Tanksley</name>
</author>
<author><name sortKey="Chen, X" uniqKey="Chen X">X Chen</name>
</author>
<author><name sortKey="Coffey, Rj" uniqKey="Coffey R">RJ Coffey</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Wang, Z" uniqKey="Wang Z">Z Wang</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Kito, Y" uniqKey="Kito Y">Y Kito</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Kundu, M" uniqKey="Kundu M">M Kundu</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Seo, Jw" uniqKey="Seo J">JW Seo</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Li, J" uniqKey="Li J">J Li</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Hu, Xy" uniqKey="Hu X">XY Hu</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="He, S" uniqKey="He S">S He</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Choi, Dw" uniqKey="Choi D">DW Choi</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Hingorani, Sr" uniqKey="Hingorani S">SR Hingorani</name>
</author>
</analytic>
</biblStruct>
</listBibl>
</div1>
</back>
</TEI>
</record>
Pour manipuler ce document sous Unix (Dilib)
EXPLOR_STEP=$WICRI_ROOT/Sante/explor/ChloroquineV1/Data/Ncbi/Curation
HfdSelect -h $EXPLOR_STEP/biblio.hfd -nk 000E52 | SxmlIndent | more
Ou
HfdSelect -h $EXPLOR_AREA/Data/Ncbi/Curation/biblio.hfd -nk 000E52 | SxmlIndent | more
Pour mettre un lien sur cette page dans le réseau Wicri
{{Explor lien |wiki= Sante |area= ChloroquineV1 |flux= Ncbi |étape= Curation |type= RBID |clé= PMC:6971022 |texte= NEDD4L downregulates autophagy and cell growth by modulating ULK1 and a glutamine transporter }}
Pour générer des pages wiki
HfdIndexSelect -h $EXPLOR_AREA/Data/Ncbi/Curation/RBID.i -Sk "pubmed:31959741" \ | HfdSelect -Kh $EXPLOR_AREA/Data/Ncbi/Curation/biblio.hfd \ | NlmPubMed2Wicri -a ChloroquineV1
![]() | This area was generated with Dilib version V0.6.33. | ![]() |