The DOI matches its Crossref record; 146 of the 146 references it cites were found in a registry or an index.
Hypoxia signalling through mTOR and the unfolded protein response in cancer
Abstract
Hypoxia occurs in the majority of tumours, promoting angiogenesis, metastasis and resistance to therapy. Responses to hypoxia are orchestrated in part through activation of the hypoxia-inducible factor family of transcription factors (HIFs). Recently, two additional O(2)-sensitive signalling pathways have also been implicated: signalling through the mammalian target of rapamycin (mTOR) kinase and signalling through activation of the unfolded protein response (UPR). Although they are activated independently, growing evidence suggests that HIF-, mTOR- and UPR-dependent responses to hypoxia act in an integrated way, influencing each other and common downstream pathways that affect gene expression, metabolism, cell survival, tumorigenesis and tumour growth.
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In the citing paper
“These adaptations include increased amino acid transporter activity and enzyme expression to boost the concentration of glutathione, the principal intracellular antioxidant, stimulation of hematopoiesis, and upregulation of the angiogenic growth factor VEGF.”
From Placental Origins of Chronic Disease (2016) · cites this paper as [585]
In the citing paper
“It also upregulates the transcription factor ATF4, which along with the ATF6 and IRE1 pathways selectively regulates gene expression to assist the cell to tolerate hypoxia (180, 343, 585).”
From Placental Origins of Chronic Disease (2016) · cites this paper as [585]
In the citing paper
“There are two principal mechanisms that operate, a rapid response involving phosphorylation of eIF2α through PERK and the UPR, and a longer term response dependent on suppression of the mTOR pathway (181, 585).”
From Placental Origins of Chronic Disease (2016) · cites this paper as [585]
Citations
Cites
2 retracted
Mitochondrial Autophagy Is an HIF-1-dependent Adaptive Metabolic Response to Hypoxia
Zhang, H., Bosch-Marce, M., Shimoda, L. A., Tan, Y. S., Baek, J. H., Wesley, J. B., Gonzalez, F. J., & Semenza, G. L. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m800102200 · Cited by 1,601
RetractedProapoptotic BAX and BAK Modulate the Unfolded Protein Response by a Direct Interaction with IRE1α
Hetz, C. A., Bernasconi, P., Fisher, J. K., Lee, A., Bassik, M. C., Antonsson, B. E., Brandt, G. S., Iwakoshi, N. N., Schinzel, A. C., Glimcher, L. H., et al. (2006) · Science · doi:10.1126/science.1123480 · Cited by 688
RetractedTargeting HIF-1 for cancer therapy
Semenza, G. L. (2003) · Nature Reviews Cancer · doi:10.1038/nrc1187 · Cited by 6,717
Signal integration in the endoplasmic reticulum unfolded protein response
Ron, D., & Walter, P. (2007) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2199 · Cited by 6,431
Upstream and downstream of mTOR
Hay, N., & Sonenberg, N. (2004) · Genes & Development · doi:10.1101/gad.1212704 · Cited by 4,181
Autophagy: process and functionPreprint
Mizushima, N. (2007) · Genes & Development · doi:10.1101/gad.1599207 · Cited by 4,104
The Biology of Cancer: Metabolic Reprogramming Fuels Cell Growth and Proliferation
DeBerardinis, R. J., Lum, J. J., Hatzivassiliou, G., & Thompson, C. B. (2008) · Cell Metabolism · doi:10.1016/j.cmet.2007.10.002 · Cited by 4,088
Endoplasmic Reticulum Stress Links Obesity, Insulin Action, and Type 2 Diabetes
Özcan, U., Cao, Q., Yilmaz, E., Lee, A.-H., Iwakoshi, N. N., Özdelen, E., Tuncman, G., Görgün, C., Glimcher, L. H., & Hotamisligil, G. S. (2004) · Science · doi:10.1126/science.1103160 · Cited by 3,844
An Integrated Stress Response Regulates Amino Acid Metabolism and Resistance to Oxidative Stress
Harding, H. P., Zhang, Y., Zeng, H., Novoa, I., Lu, P. D., Calfon, M. A., Sadri, N., Yun, C., Popko, B., Paules, R. S., et al. (2003) · Molecular Cell · doi:10.1016/s1097-2765(03)00105-9 · Cited by 3,336
Defining the role of mTOR in cancer
Guertin, D. A., & Sabatini, D. M. (2007) · Cancer Cell · doi:10.1016/j.ccr.2007.05.008 · Cited by 2,833
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Regulation of cancer cell metabolism
Cairns, R. A., Harris, I. S., & Mak, T. W. (2011) · Nature Reviews Cancer · doi:10.1038/nrc2981 · Cited by 4,744
Reactive oxygen species in cancer
Liou, G., & Störz, P. (2010) · Free Radical Research · doi:10.3109/10715761003667554 · Cited by 3,528
Targeting hypoxia in cancer therapy
Wilson, W. R., & Hay, M. P. (2011) · Nature Reviews Cancer · doi:10.1038/nrc3064 · Cited by 3,172
Hypoxia-inducible factors and the response to hypoxic stress
Majmundar, A. J., Wong, W. J., & Simon, M. C. (2010) · Molecular Cell · doi:10.1016/j.molcel.2010.09.022 · Cited by 2,380
Laplante, M., & Sabatini, D. M. (2009) · Journal of Cell Science · doi:10.1242/jcs.051011 · Cited by 2,284
Metadata
- Authors
- Wouters, B. G., & Koritzinsky, M.
- Affiliations
- University Health Network (CA)
- Corresponding author
- Wouters, Bradly G.
- Venue
- Nature Reviews Cancer
- Published
- 2008-10-10
- Volume
- 8
- Issue
- 11
- Pages
- 851-864
- ISSN
- 1474-175X (ISSN-L)
- 1474-1768
- OpenAlex
- W1978301900
- Cited by
- 894
- References
- 146
- Citations by year
- 2026: 16 · 2025: 47 · 2024: 27 · 2023: 30 · 2022: 31 · 2021: 48 · 2020: 39 · 2019: 56 · 2018: 54 · 2017: 46 · 2016: 62 · 2015: 63 · 2014: 68 · 2013: 66 · 2012: 73
- FWCI
- 4.00
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature reviews. Cancer (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
- Keywords
- hypoxia signaling, mTOR, unfolded protein response, hypoxia-inducible factor, tumor hypoxia, angiogenesis, metastasis, treatment resistance, cancer metabolism, carcinogenesis, tumor growth
- MeSH terms
- Humans, Neoplasms, Protein Kinases, Signal Transduction, Cell Hypoxia, Protein Folding, Hypoxia-Inducible Factor 1, alpha Subunit, TOR Serine-Threonine Kinases
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