FOXO3a-dependent regulation of Pink1 (Park6) mediates survival signaling in response to cytokine deprivation
Open accessAbstract
Loss-of-function mutations of phosphatase/tensin homolog deleted on chromosome 10 (PTEN)-induced putative kinase 1 (Pink1) (also known as Park6) identified in familial forms of Parkinson's disease (PD) are associated with compromised mitochondrial function. Emerging data suggest that Pink1 is an essential pro-survival factor that is induced in response to oxidative stress. However, the mechanisms regulating Pink1 expression under stress conditions remain unknown. Forkhead box, subgroup O (FOXO) transcription factors carry out distinct biological functions in response to different extracellular signals. Notably, FOXO factors possess evolutionarily conserved roles in protecting cells from oxidative stress-induced death. Here we report that the FOXO family member FOXO3a controls Pink1 transcription in both mouse and human cells subjected to growth factor deprivation and that this regulation is exerted through evolutionarily conserved FOXO binding elements. Induction of Pink1 by FOXO3a is crucial for survival signals in lymphocytes, as depletion of Pink1 sensitizes these cells to death induced by deprivation of an essential growth factor. Our data reveal that the role of FOXO factors in protecting cells from growth factor deprivation-triggered apoptosis has been underestimated and that FOXOs mediate this protection by transactivating anti-apoptotic effectors like Pink1. Given the essential role of Pink1 in combating cell death, our findings may help to dissect the mechanisms by which FOXO proteins function as anti-oxidative stress factors.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
FOXOs can act as critical regulators of mitochondrial homeostasis by regulating the expression of Mul1 and PINK1.
“Interestingly, FOXOs can also act as critical regulators of mitochondrial homeostasis through, at least, two additional means: (i) by regulating the expression of Mul1, a mitochondrial E3 ubiquitin ligase that controls Mfn2 degradation rates (Lokireddy et al, 2012), and (ii) by regulating the expression of the PTEN-induced kinase 1 (PINK1), a key component of the mitophagy machinery (Mei et al, 2”
From Mitochondrial response to nutrient availability and its role in metabolic disease (2014) · cites this paper as Mei et al, 2009
Cites
Hereditary Early-Onset Parkinson's Disease Caused by Mutations in <i>PINK1</i>
Valente, E. M., Abou-Sleiman, P. M., Caputo, V., Muqit, M. M. K., Harvey, K., Gispert, S., Ali, Z., Del Turco, D., Bentivoglio, A. R., Healy, D. G., et al. (2004) · Science · doi:10.1126/science.1096284 · Cited by 3,481 · see citing works
Drosophila pink1 is required for mitochondrial function and interacts genetically with parkin
Clark, I. E., Dodson, M. W., Jiang, C., Cao, J. H., Huh, J. R., Seol, J. H., Yoo, S. J., Hay, B. A., & Guo, M. (2006) · Nature · doi:10.1038/nature04779 · Cited by 1,788 · see citing works
Forkhead transcription factor FOXO3a protects quiescent cells from oxidative stress
Kops, G. J. P. L., Dansen, T. B., Polderman, P. E., Saarloos, I., Wirtz, K. W. A., Coffer, P. J., Huang, T.-T., Bos, J. L., Medema, R. H., & Burgering, B. M. T. (2002) · Nature · doi:10.1038/nature01036 · Cited by 1,580 · see citing works
FoxOs Are Critical Mediators of Hematopoietic Stem Cell Resistance to Physiologic Oxidative Stress
Tothova, Z., Kollipara, R., Huntly, B. J., Lee, B. H., Castrillon, D. H., Cullen, D. E., McDowell, E. P., Lazo-Kallanian, S., Williams, I. R., Sears, C., et al. (2007) · Cell · doi:10.1016/j.cell.2007.01.003 · Cited by 1,562 · see citing works
Lin, K., Dorman, J. B., Rodan, A. R., & Kenyon, C. J. (1997) · Science · doi:10.1126/science.278.5341.1319 · Cited by 1,496 · see citing works
Clements, C. M., McNally, R. S., Conti, B. J., Mak, T. W., & Ting, J. P.-Y. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0607260103 · Cited by 818 · see citing works
Self-citationRedox Regulation of Forkhead Proteins Through a <i>p66shc</i> -Dependent Signaling Pathway
Nemoto, S., & Finkel, T. (2002) · Science · doi:10.1126/science.1069004 · Cited by 818 · see citing works
Yang, Y., Gehrke, S., Imai, Y., Huang, Z., Ouyang, Y., Wang, J.-W., Yang, L., Beal, M. F., Vogel, H., & Lu, B. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0602493103 · Cited by 798 · see citing works
Functional Interaction Between ß-Catenin and FOXO in Oxidative Stress Signaling
Essers, M. A. G., Smits, L. M. M., Barker, N., Polderman, P. E., Burgering, B. M. T., & Korswagen, H. C. (2005) · Science · doi:10.1126/science.1109083 · Cited by 741 · see citing works
Loss of PINK1 causes mitochondrial functional defects and increased sensitivity to oxidative stress
Gautier, C. A., Kitada, T., & Shen, J. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0802076105 · Cited by 698 · see citing works
FoxO transcription factors in the maintenance of cellular homeostasis during aging
Salih, D. A., & Brunet, A. (2008) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2008.02.005 · Cited by 604 · see citing works
PINK1 Protects against Oxidative Stress by Phosphorylating Mitochondrial Chaperone TRAP1
Pridgeon, J. W., Olzmann, J. A., Chin, L.-S., & Li, L. (2007) · PLoS Biology · doi:10.1371/journal.pbio.0050172 · Cited by 596 · see citing works
T Cell-Specific Loss of Pten Leads to Defects in Central and Peripheral Tolerance
Suzuki, A., Tsukio, M., Ohteki, T., Sasaki, T., Kaisho, T., Kimura, Y., Yoshida, R., Wakeham, A. C., Higuchi, T., Fukumoto, M., et al. (2001) · Immunity · doi:10.1016/s1074-7613(01)00134-0 · Cited by 589 · see citing works
Self-citationLong-Lived Drosophila with Overexpressed dFOXO in Adult Fat Body
Giannakou, M. E., Goss, M. W., Jünger, M. A., Hafen, E., Leevers, S. J., & Partridge, L. (2004) · Science · doi:10.1126/science.1098219 · Cited by 577 · see citing works
MacKeigan, J. P., Murphy, L. O., & Blenis, J. (2005) · Nature Cell Biology · doi:10.1038/ncb1258 · Cited by 561 · see citing works
Almeida, M., Li, H., Martín-Millán, M., O’Brien, C. A., & Manolagas, S. C. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m702811200 · Cited by 546 · see citing works
The mitochondrial protease HtrA2 is regulated by Parkinson's disease-associated kinase PINK1
Plun‐Favreau, H., Klupsch, K., Moisoi, N., Gandhi, S., Kjaer, S., Frith, D., Harvey, K., Deas, E., Harvey, R. J., McDonald, N. Q., et al. (2007) · Nature Cell Biology · doi:10.1038/ncb1644 · Cited by 476 · see citing works
FOXO3a-dependent regulation of Puma in response to cytokine/growth factor withdrawal
You, H., Pellegrini, M., Tsuchihara, K., Yamamoto, K., Häcker, G. A., Erlacher, M., Villunger, A., & Mak, T. W. (2006) · The Journal of Experimental Medicine · doi:10.1084/jem.20060353 · Cited by 413 · see citing works
Self-citationGrowth-suppressive effects of BPOZ and EGR2, two genes involved in the PTEN signaling pathway
Unoki, M., & Nakamura, Y. (2001) · Oncogene · doi:10.1038/sj.onc.1204608 · Cited by 382 · see citing works
Petit-Paitel, A., Kawarai, T., Paitel, E., Sanjo, N., Maj, M. C., Scheid, M. P., Chen, F., Gu, Y., Hasegawa, H., Salehi‐Rad, S., et al. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m505143200 · Cited by 329 · see citing works
PINK1 is necessary for long term survival and mitochondrial function in human dopaminergic neurons
Wood-Kaczmar, A., Gandhi, S., Yao, Z., Abramov, A. S. Y., Miljan, E. A., Keen, G., Stanyer, L., Hargreaves, I., Klupsch, K., Deas, E., et al. (2008) · PLoS ONE · doi:10.1371/journal.pone.0002455 · Cited by 316 · see citing works
Interaction of FOXO with β-Catenin Inhibits β-Catenin/T Cell Factor Activity
Hoogeboom, D., Essers, M. A. G., Polderman, P. E., Voets, E., Smits, L. M. M., & Burgering, B. M. T. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m706638200 · Cited by 268 · see citing works
Association of PINK1 and DJ-1 confers digenic inheritance of early-onset Parkinson's disease
Tang, B., Xiong, H., Sun, P., Zhang, Y., Wang, D., Hu, Z., Zhu, Z.-H., Ma, H., Pan, Q., Xia, J., et al. (2006) · Human Molecular Genetics · doi:10.1093/hmg/ddl104 · Cited by 213 · see citing works
Self-citationBiggs, W., & Cavenee, W. K. (2001) · Mammalian Genome · doi:10.1007/s003350020002 · Cited by 210 · see citing works
Antioxidants protect PINK1 -dependent dopaminergic neurons in Drosophila
Wang, D., Li, Q., Xiong, H., Liu, J., Neckameyer, W. S., Oldham, S., Xia, K., Wang, J., Bodmer, R., & Zhang, Z. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0604661103 · Cited by 196 · see citing works
Small interfering RNA targeting the PINK1 induces apoptosis in dopaminergic cells SH-SY5Y
Deng, H., Jankovic, J. J., Guo, Y., Xie, W., & Le, W. (2005) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2005.09.178 · Cited by 156 · see citing works
Self-citationRegulation of transactivation-independent proapoptotic activity of p53 by FOXO3a
You, H., Yamamoto, K., & Mak, T. W. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0600889103 · Cited by 149 · see citing works
Self-citationp53-dependent inhibition of FKHRL1 in response to DNA damage through protein kinase SGK1
You, H., Jang, Y., You-Ten, A. I., Okada, H., Silvester, J., Wakeham, A. C., Zaugg, K., & Mak, T. W. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0406286101 · Cited by 127 · see citing works
Self-citationGlutathione in Parkinson's disease: A link between oxidative stress and mitochondrial damage?
Monte, D. A. D., Chan, P., & Sandy, M. S. (1992) · Annals of Neurology · doi:10.1002/ana.410320719 · Cited by 107 · see citing works
Hyde, H., Borthwick, N., Janossy, G., Salmon, M., & Akbar, A. N. (1997) · Blood · doi:10.1182/blood.v89.7.2453 · Cited by 29 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Modulation of oxidative stress as an anticancer strategy
Gorrini, C., Harris, I. S., & Mak, T. W. (2013) · Nature Reviews Drug Discovery · doi:10.1038/nrd4002 · Cited by 3,579 · see citing works
Self-citationKume, S., Uzu, T., Horiike, K., Chin-Kanasaki, M., Isshiki, K., Araki, S.-I., Sugimoto, T., Haneda, M., Kashiwagi, A., & Koya, D. (2010) · Journal of Clinical Investigation · doi:10.1172/jci41376 · Cited by 640 · see citing works
PTEN-inducible kinase 1 (PINK1)/Park6 is indispensable for normal heart function
Billia, F., Hauck, L., Konecny, F., Rao, V., Shen, J., & Mak, T. W. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1106291108 · Cited by 414 · see citing works
Self-citationKung-Chun Chiu, D., Pui-Wah Tse, A., Law, C.-T., Ming-Jing Xu, I., Lee, D., Chen, M., Kit-Ho Lai, R., Wai-Hin Yuen, V., Wing-Sum Cheu, J., Wai-Hung Ho, D., et al. (2019) · Cell Death & Disease · doi:10.1038/s41419-019-2155-3 · Cited by 192 · see citing works
Das, S., Mitrovsky, G., Vasanthi, H. R., & Das, D. K. (2014) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2014/345105 · Cited by 173 · see citing works
RetractedAudesse, A. J., Dhakal, S., Hassell, L.-A., Gardell, Z., Nemtsova, Y., & Webb, A. E. (2019) · PLOS Genetics · doi:10.1371/journal.pgen.1008097 · Cited by 155 · see citing works
FoxO1 Promotes Mitophagy in the Podocytes of Diabetic Male Mice via the PINK1/Parkin Pathway
Li, W., Du, M., Wang, Q., Ma, X., Wu, L., Guo, F., Ji, H., Huang, F., & Qin, G. (2017) · Endocrinology · doi:10.1210/en.2016-1970 · Cited by 146 · see citing works
Mitochondrial response to nutrient availability and its role in metabolic disease
Gao, A. W., Cantó, C., & Houtkooper, R. H. (2014) · EMBO Molecular Medicine · doi:10.1002/emmm.201303782 · Cited by 148 · see citing works
Bartolomé, A., García-Aguilar, A., Asahara, S.-I., Kido, Y., Guillén, C., Pajvani, U. B., & Benito, M. (2017) · Molecular and Cellular Biology · doi:10.1128/mcb.00441-17 · Cited by 141 · see citing works
Mitochondrial quality control by the Pink1/Parkin system
Rüb, C., Wilkening, A., & Voos, W. (2017) · Cell and Tissue Research · doi:10.1007/s00441-016-2485-8 · Cited by 132 · see citing works
PINK1: The guard of mitochondria
Wang, N., Zhu, P., Huang, R., Wang, C., Sun, L., Lan, B., He, Y., Zhao, H., & Gao, Y. (2020) · Life Sciences · doi:10.1016/j.lfs.2020.118247 · Cited by 107 · see citing works
ApoE4 attenuates autophagy via FoxO3a repression in the brain
Sohn, H.-Y., Kim, S.-I., Park, J.-Y., Park, S.-H., Koh, Y. H., Kim, J., & Jo, C. (2021) · Scientific Reports · doi:10.1038/s41598-021-97117-6 · Cited by 54 · see citing works
Regulation of mitochondrial function by forkhead transcription factors
Jerome, M. S., Kuthethur, R., Kabekkodu, S. P., & Chakrabarty, S. (2022) · Biochimie · doi:10.1016/j.biochi.2022.03.013 · Cited by 33 · see citing works
- Authors
- Mei, Y., Zhang, Y., Yamamoto, K., Xie, W., Mak, T. W., & You, H.
- Affiliations
- Xiamen University (CN)
- Princess Margaret Cancer Centre (CA)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2009-03-31
- Volume
- 106
- Issue
- 13
- Pages
- 5153-5158
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC2654023
- OpenAlex
- W2001469924
- Cited by
- 172
- References
- 30
- Citations by year
- 2026: 11 · 2025: 5 · 2024: 3 · 2023: 11 · 2022: 11 · 2021: 15 · 2020: 9 · 2019: 8 · 2018: 13 · 2017: 13 · 2016: 9 · 2015: 7 · 2014: 10 · 2013: 7 · 2012: 12
- FWCI
- 5.23
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China
- School of Medicine, Stanford University
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › FOXO transcription factor regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Keywords
- FOXO3, PINK1, PARK6, transcriptional regulation, cytokine deprivation, growth factor deprivation, apoptosis, cell survival signaling, lymphocytes, oxidative stress, Parkinson's disease, mitochondrial function
- MeSH terms
- Forkhead Box Protein O3, PTEN-Induced Putative Kinase, Animals, Cell Line, Cell Survival, Humans, Lymphocytes, Protein Kinases, Transcriptional Activation, Conserved Sequence, Oxidative Stress, Regulatory Elements, Transcriptional, Mice, Forkhead Transcription Factors
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
