TSC2 regulates VEGF through mTOR-dependent and -independent pathways
Open accessAbstract
Inactivation of the TSC2 tumor suppressor protein causes tuberous sclerosis complex (TSC), a disease characterized by highly vascular tumors. TSC2 has multiple functions including inhibition of mTOR (mammalian target of Rapamycin). We found that TSC2 regulates VEGF through mTOR-dependent and -independent pathways. TSC2 loss results in the accumulation of HIF-1alpha and increased expression of HIF-responsive genes including VEGF. Wild-type TSC2, but not a disease-associated TSC2 mutant, downregulates HIF. Rapamycin normalizes HIF levels in TSC2(-/-) cells, indicating that TSC2 regulates HIF by inhibiting mTOR. In contrast, Rapamycin only partially downregulates VEGF in this setting, implying an mTOR-independent link between TSC2 loss and VEGF. This pathway may involve chromatin remodeling since the HDAC inhibitor Trichostatin A downregulates VEGF in TSC2(-/-) cells.
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?
Inactivating mutations in PTEN or TSC, as well as activating mutations in PI3K or AKT, lead to increased TORC1 activity that promotes HIF-α stabilization.
“Inactivating mutations in phosphatase and tensin homolog (PTEN) or the tuberosis sclerosis complex (TSC) complex, as well as activating mutations in phosphatidylinositol 3-kinase (PI3K) or AKT, lead to increased TORC1 activity that promotes HIF-α stabilization”
From Hypoxic control of metastasis (2016) · cites this paper as [30]
Cites
1 retracted
Dan, H. C., Sun, M., Yang, L., Feldman, R. I., Sui, X.-M., Ou, C. C., Nellist, M. D., Yeung, R. S. W., Halley, D. J. J., Nicosia, S. V., et al. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m205838200 · Cited by 370 · see citing works
RetractedJaakkola, P., Mole, D. R., Tian, Y.-M., Wilson, M. I., Gielbert, J., Gaskell, S. J., Kriegsheim, A. V., Hebestreit, H. F., Mukherji, M., Schofield, C. J., et al. (2001) · Science · doi:10.1126/science.1059796 · Cited by 5,535 · see citing works
The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis
Maxwell, P. H., Wiesener, M. S., Chang, G.-W., Clifford, S. C., Vaux, E. C., Cockman, M. E., Wykoff, C. C., Pugh, C. W., Maher, E. R., & Ratcliffe, P. J. (1999) · Nature · doi:10.1038/20459 · Cited by 5,180 · see citing works
Ivan, M., Kondo, K., Yang, H., Kim, W., Valiando, J., Ohh, M., Salic, A., Asara, J. M., Lane, W. S., & Kaelin Jr., W. G. (2001) · Science · doi:10.1126/science.1059817 · Cited by 4,735 · see citing works
Self-citationEpstein, A. C. R., Gleadle, J. M., McNeill, L. A., Hewitson, K. S., O'Rourke, J., Mole, D. R., Mukherji, M., Metzen, E., Wilson, M. I., Dhanda, A., et al. (2001) · Cell · doi:10.1016/s0092-8674(01)00507-4 · Cited by 3,333 · see citing works
TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling
Inoki, K., Li, Y., Zhu, T., Wu, J., & Guan, K.-L. (2002) · Nature Cell Biology · doi:10.1038/ncb839 · Cited by 3,083 · see citing works
Role of HIF-1α in hypoxia-mediated apoptosis, cell proliferation and tumour angiogenesis
Carmeliet, P., Dor, Y., Herbert, J.-M., Fukumura, D., Brusselmans, K., Dewerchin, M., Neeman, M., Bono, F., Abramovitch, R., Maxwell, P., et al. (1998) · Nature · doi:10.1038/28867 · Cited by 2,502 · see citing works
Addiction to Oncogenes--the Achilles Heal of Cancer
Weinstein, I. (2002) · Science · doi:10.1126/science.1073096 · Cited by 1,753 · see citing works
Guba, M. O., von Breitenbuch, P., Steinbauer, M. G. M., Koehl, G. E., Flegel, S., Hornung, M., Bruns, C. J., Zuelke, C., Farkas, S. A., Anthuber, M., et al. (2002) · Nature Medicine · doi:10.1038/nm0202-128 · Cited by 1,739 · see citing works
Identification and characterization of the tuberous sclerosis gene on chromosome 16
(1993) · Cell · doi:10.1016/0092-8674(93)90618-z · Cited by 1,645 · see citing works
Manning, B. D., Tee, A. R., Logsdon, M. N., Blenis, J., & Cantley, L. C. (2002) · Molecular Cell · doi:10.1016/s1097-2765(02)00568-3 · Cited by 1,555 · see citing works
Regulation of translation initiation by FRAP/mTOR
Gingras, A.-C., Raught, B., & Sonenberg, N. (2001) · Genes & Development · doi:10.1101/gad.887201 · Cited by 1,545 · see citing works
VEGF and the quest for tumour angiogenesis factors
Ferrara, N. (2002) · Nature Reviews Cancer · doi:10.1038/nrc909 · Cited by 1,536 · see citing works
(2000) · PubMed · Cited by 1,445 · see citing works
Definition of Two Angiogenic Pathways by Distinct α v Integrins
Friedlander, M., Brooks, P. C., Shaffer, R. W., Kincaid, C. M., Varner, J. A., & Cheresh, D. A. (1995) · Science · doi:10.1126/science.270.5241.1500 · Cited by 1,310 · see citing works
Laughner, E., Taghavi, P., Chiles, K., Mahon, P. C., & Semenza, G. L. (2001) · Molecular and Cellular Biology · doi:10.1128/mcb.21.12.3995-4004.2001 · Cited by 1,256 · see citing works
Hudson, C. C., Liu, M., Chiang, G. G., Otterness, D. M., Loomis, D. C., Kaper, F., Giaccia, A. J., & Abraham, R. T. (2002) · Molecular and Cellular Biology · doi:10.1128/mcb.22.20.7004-7014.2002 · Cited by 1,186 · see citing works
Regulation of tumor angiogenesis by p53-induced degradation of hypoxia-inducible factor 1alpha.
Ravi, R. K., Mookerjee, B., Bhujwalla, Z. M., Sutter, T. R., Artemov, D., Zeng, Q., Dillehay, L. E., Madan, A., Semenza, G. L., & Bedi, A. (2000) · PubMed Central · Cited by 1,099 · see citing works
Insulin Activation of Rheb, a Mediator of mTOR/S6K/4E-BP Signaling, Is Inhibited by TSC1 and 2
Garami, A., Zwartkruis, F. J. T., Nobukuni, T., Joaquin, M., Roccio, M., Stocker, H., Kozma, S. C., Hafen, E., Bos, J. L., & Thomas, G. (2003) · Molecular Cell · doi:10.1016/s1097-2765(03)00220-x · Cited by 1,043 · see citing works
Masson, N., Willam, C., Maxwell, P. H., Pugh, C. W., & Ratcliffe, P. J. (2001) · The EMBO Journal · doi:10.1093/emboj/20.18.5197 · Cited by 1,014 · see citing works
Enhanced sensitivity of PTEN-deficient tumors to inhibition of FRAP/mTOR
Neshat, M. S., Mellinghoff, I. K., Tran, C., Stiles, B. L., THOMAS, G. V., Petersen, R., Frost, P., Gibbons, J. J., Wu, H., & Sawyers, C. L. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.171076798 · Cited by 968 · see citing works
Regulation of tumor angiogenesis by p53-induced degradation of hypoxia-inducible factor 1α
Ravi, R., Mookerjee, B., Bhujwalla, Z. M., Sutter, C. H., Artemov, D., Zeng, Q., Dillehay, L. E., Madan, A., Semenza, G. L., & Bedi, A. (2000) · Genes & Development · doi:10.1101/gad.14.1.34 · Cited by 967 · see citing works
Akt regulates growth by directly phosphorylating Tsc2
Potter, C. J., Pedraza, L. G., & Xu, T. (2002) · Nature Cell Biology · doi:10.1038/ncb840 · Cited by 959 · see citing works
The splice variants of vascular endothelial growth factor (VEGF) and their receptors
Robinson, C. J., & Stringer, S. E. (2001) · Journal of Cell Science · doi:10.1242/jcs.114.5.853 · Cited by 944 · see citing works
Molecular basis of the VHL hereditary cancer syndrome
Kaelin, W. G. (2002) · Nature Reviews Cancer · doi:10.1038/nrc885 · Cited by 865 · see citing works
Self-citationLoss of <i>PTEN</i> facilitates HIF-1-mediated gene expression
Zundel, W., Schindler, C., Haas-Kogan, D., Koong, A., Kaper, F., Chen, E., Gottschalk, A. R., Ryan, H. E., Johnson, R. S., Jefferson, A. B., et al. (2000) · Genes & Development · doi:10.1101/gad.14.4.391 · Cited by 840 · see citing works
Tee, A. R., Fingar, D. C., Manning, B. D., Kwiatkowski, D. J., Cantley, L. C., & Blenis, J. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.202476899 · Cited by 827 · see citing works
HIF-1α binding to VHL is regulated by stimulus-sensitive proline hydroxylation
Yu, F., White, S. B., Zhao, Q., & Lee, F. S. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.181341498 · Cited by 796 · see citing works
Richard, D. E., Berra, E., Gothié, E., Roux, D., & Pouysségur, J. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.46.32631 · Cited by 790 · see citing works
Inhibition of HIF is necessary for tumor suppression by the von Hippel-Lindau protein
Kondo, K., Klco, J., Nakamura, E., Lechpammer, M., & Kaelin, W. G. (2002) · Cancer Cell · doi:10.1016/s1535-6108(02)00043-0 · Cited by 761 · see citing works
Self-citationHistone deacetylases induce angiogenesis by negative regulation of tumor suppressor genes
Kim, M. S., Kwon, H. J., Lee, Y. M., Baek, J. H., Jang, J.-E., Lee, S.-W., Moon, E.-J., Kim, H.-S., Lee, S., Chung, H. Y., et al. (2001) · Nature Medicine · doi:10.1038/86507 · Cited by 732 · see citing works
Kwiatkowski, D. J. (2002) · Human Molecular Genetics · doi:10.1093/hmg/11.5.525 · Cited by 663 · see citing works
Rheb promotes cell growth as a component of the insulin/TOR signalling network
Saucedo, L. J., Gao, X., Chiarelli, D. A., Li, L., Pan, D., & Edgar, B. A. (2003) · Nature Cell Biology · doi:10.1038/ncb996 · Cited by 658 · see citing works
Transcription Factor HIF-1 Is a Necessary Mediator of the Pasteur Effect in Mammalian Cells
Seagroves, T. N., Ryan, H. E., Lu, H., Wouters, B. G., Knapp, M., Thibault, P., Laderoute, K. R., & Johnson, R. S. (2001) · Molecular and Cellular Biology · doi:10.1128/mcb.21.10.3436-3444.2001 · Cited by 634 · see citing works
Insulin induces transcription of target genes through the hypoxia‐inducible factor HIF‐1α/ARNT
Zelzer, E., Levy, Y., Kahana, C., Shilo, B., Rubinstein, M., & Cohen, B. (1998) · The EMBO Journal · doi:10.1093/emboj/17.17.5085 · Cited by 575 · see citing works
An inhibitor of mTOR reduces neoplasia and normalizes p70/S6 kinase activity in Pten +/− mice
Podsypanina, K., Lee, R. T., Politis, C., Hennessy, I., Crane, A., Puc, J., Neshat, M. S., Wang, H., Yang, L., Gibbons, J., et al. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.171060098 · Cited by 568 · see citing works
(2001) · PubMed · Cited by 557 · see citing works
Treins, C., Giorgetti‐Peraldi, S., Murdaca, J., Semenza, G. L., & OBBERGHEN, E. V. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m204152200 · Cited by 535 · see citing works
Jiang, B., Agani, F. H., Passaniti, A., & Semenza, G. L. (1997) · PubMed · Cited by 532 · see citing works
Rheb is an essential regulator of S6K in controlling cell growth in Drosophila
Stocker, H., Radimerski, T., Schindelholz, B., Wittwer, F., Belawat, P., Daram, P., Breuer, S., Thomas, G., & Hafen, E. (2003) · Nature Cell Biology · doi:10.1038/ncb995 · Cited by 530 · see citing works
Maher, E. R., & Kaelin, W. G. (1997) · Medicine · doi:10.1097/00005792-199711000-00001 · Cited by 529 · see citing works
Self-citationIdentification of a conserved motif required for mTOR signaling.
Schalm, S., & Blenis, J. (2002) · Current Biology · doi:10.1016/s0960-9822(02)00762-5 · Cited by 507 · see citing works
TSC1 and TSC2 tumor suppressors antagonize insulin signaling in cell growth.Preprint
Gao, X., & Pan, D. (2001) · Genes & Development · doi:10.1101/gad.901101 · Cited by 484 · see citing works
Maranchie, J. K., Vasselli, J. R., Riss, J., Bonifacino, J. S., Linehan, W. M., & Klausner, R. D. (2002) · Cancer Cell · doi:10.1016/s1535-6108(02)00044-2 · Cited by 433 · see citing works
Tuberin Regulates p70 S6 Kinase Activation and Ribosomal Protein S6 Phosphorylation
Goncharova, E., Goncharov, D. A., Eszterhas, A., Hunter, D., Glassberg, M., Yeung, R. S., Walker, C., Noonan, D., Kwiatkowski, D., Chou, M. M., et al. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m202678200 · Cited by 433 · see citing works
Vascular tumors in livers with targeted inactivation of the von Hippel–Lindau tumor suppressor
Haase, V. H., Glickman, J. N., Socolovsky, M., & Jaenisch, R. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.98.4.1583 · Cited by 421 · see citing works
Onda, H., Lueck, A., Marks, P. W., Warren, H. B., & Kwiatkowski, D. J. (1999) · Journal of Clinical Investigation · doi:10.1172/jci7319 · Cited by 391 · see citing works
Molecular genetic advances in tuberous sclerosis
Cheadle, J. P., Reeve, M. P., Sampson, J. R., & Kwiatkowski, D. J. (2000) · Human Genetics · doi:10.1007/s004390000348 · Cited by 350 · see citing works
Milanini, J., Viñals, F., Pouysségur, J., & Pagès, G. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.29.18165 · Cited by 315 · see citing works
Wiesener, M. S., Münchenhagen, P., Berger, I., Morgan, N. V., Roigas, J., Schwiertz, A., Jürgensen, J. S., Gruber, G., Maxwell, P. H., Löning, S. A., et al. (2001) · PubMed · Cited by 308 · see citing works
Yeung, R. S. W., Xiao, G. H., Jin, F., Lee, W. C., Testa, J. R., & Knudson, A. G. (1994) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.91.24.11413 · Cited by 307 · see citing works
Maity, A. M., Pore, N., Lee, J. S. H., Solomon, D., & O’Rourke, D. M. (2000) · PubMed · Cited by 306 · see citing works
Stiehl, D. P., JELKMANN, W. E. B., Wenger, R. H., & Hellwig‐Bürgel, T. (2002) · FEBS Letters · doi:10.1016/s0014-5793(02)02247-0 · Cited by 285 · see citing works
Kenerson, H. L., Aicher, L. D., True, L. D., & Yeung, R. S. W. (2002) · PubMed · Cited by 282 · see citing works
Mayerhofer, M., Valent, P., Sperr, W. R., Griffin, J. D., & Sillaber, C. (2002) · Blood · doi:10.1182/blood-2002-01-0109 · Cited by 272 · see citing works
Kobayashi, T., Minowa, O., Kuno, J., Mitani, H., Hino, O., & Noda, T. (1999) · PubMed · Cited by 272 · see citing works
Kobayashi, T., Minowa, O., Sugitani, Y., Takai, S., Mitani, H., Kobayashi, E., Noda, T., & Hino, O. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.151033798 · Cited by 251 · see citing works
Pedram, A., Razandi, M., & Levin, E. R. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.41.26722 · Cited by 214 · see citing works
Jaeschke, A., Hartkamp, J., Saitoh, M., Roworth, W., Nobukuni, T., Hodges, A., Sampson, J. R., Thomas, G., & Lamb, R. F. (2002) · The Journal of Cell Biology · doi:10.1083/jcb.jcb.200206108 · Cited by 207 · see citing works
Pugh, C. W., & Ratcliffe, P. J. (2002) · Seminars in Cancer Biology · doi:10.1016/s1044-579x(02)00103-7 · Cited by 202 · see citing works
Lethality of Drosophila lacking TSC tumor suppressor function rescued by reducing dS6K signalingPreprint
Radimerski, T., Montagne, J., Hemmings-Mieszczak, M., & Thomas, G. (2002) · Genes & Development · doi:10.1101/gad.239102 · Cited by 186 · see citing works
Pagès, G., Berra, E., Milanini, J., Levy, A. P., & Pouysségur, J. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m002104200 · Cited by 184 · see citing works
Fredriksson, J. M., Lindquist, J. M., Bronnikov, G. E., & Nedergaard, J. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.275.18.13802 · Cited by 183 · see citing works
Arsham, A. M., Plas, D. R., Thompson, C. B., & Simon, M. C. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m111162200 · Cited by 175 · see citing works
Park, S.-K., Dadak, A. M., Haase, V. H., Fontana, L., Giaccia, A. J., & Johnson, R. S. (2003) · Molecular and Cellular Biology · doi:10.1128/mcb.23.14.4959-4971.2003 · Cited by 170 · see citing works
Chìn, K., Kurashima, Y., Ogura, T., et al. (1997) · Oncogene · doi:10.1038/sj.onc.1201201 · Cited by 164 · see citing works
Pore, N., Liu, S., Haas-Kogan, D. A., O’Rourke, D. M., & Maity, A. M. (2003) · PubMed · Cited by 147 · see citing works
Park, J. S., Qiao, L., Su, Z.-Z., Hinman, D., Willoughby, K. A., McKinstry, R. P., Yacoub, A., Duigou, G. J., Young, C. S. H., Grant, S., et al. (2001) · Oncogene · doi:10.1038/sj.onc.1204258 · Cited by 139 · see citing works
Mills, G. B., Lu, Y., & Kohn, E. C. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.191379498 · Cited by 125 · see citing works
Henry, K. W., Yuan, X., Koszewski, N. J., Onda, H., Kwiatkowski, D. J., & Noonan, D. J. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.32.20535 · Cited by 124 · see citing works
Gruden, G., Thomas, S., Burt, D. J., Lane, S. J., Chusney, G. D., Sacks, S. H., & Viberti, G. C. (1997) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.94.22.12112 · Cited by 121 · see citing works
Álvarez-Tejado, M., Alfranca, A., Aragonés, J., Vara, A., Landázuri, M. O., & del Peso, L. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m200017200 · Cited by 117 · see citing works
Co-localization of the TSC2 product tuberin with its target Rap1 in the Golgi apparatus.
Wienecke, R., Maize, J. C., Shoarinejad, F., Vass, W. C., Reed, J., Bonifacino, J. S., Resau, J., de Gunzburg, J., Yeung, R. S. W., & DeClue, J. E. (1996) · PubMed · Cited by 107 · see citing works
Rennebeck, G., Kleymenova, E., Anderson, R., Yeung, R. S. W., Artzt, K., & Walker, C. L. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.26.15629 · Cited by 107 · see citing works
Hereditary renal adenomas and adenocarcinomas in rats.
Eker, R., MOSSIGE, J. C., Johannessen, J. V., et al. (1981) · PubMed · Cited by 103 · see citing works
Nitric oxide synthase inhibition attenuates the skeletal muscle VEGF mRNA response to exercise
Gavin, T. P., Spector, D. A., Wagner, H. E., Breen, E. C., & Wagner, P. D. (2000) · Journal of Applied Physiology · doi:10.1152/jappl.2000.88.4.1192 · Cited by 93 · see citing works
Growth Signaling: TSC Takes Its Place
Marygold, S. J., & Leevers, S. J. (2002) · Current Biology · doi:10.1016/s0960-9822(02)01294-0 · Cited by 91 · see citing works
Suzuma, I., Suzuma, K., Ueki, K., Hata, Y., Feener, E. P., King, G. L., & Aiello, L. P. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m105336200 · Cited by 78 · see citing works
Liu, M. Y., Poellinger, L., & Walker, C. L. (2003) · PubMed · Cited by 73 · see citing works
Ghosh, A. K., Hirasawa, N., & Ohuchi, K. (2001) · British Journal of Pharmacology · doi:10.1038/sj.bjp.0704372 · Cited by 62 · see citing works
Involvement of p38 MAP kinase in TGF‐β‐stimulated VEGF synthesis in aortic smooth muscle cells
Yamamoto, T., Kozawa, O., Tanabe, K., et al. (2001) · Journal of Cellular Biochemistry · doi:10.1002/jcb.1179 · Cited by 54 · see citing works
Genetic and clinical aspects of familial renal neoplasms.
Iliopoulos, O., & Eng, C. (2000) · PubMed · Cited by 53 · see citing works
Analysis of the TSC1and TSC2genes in sporadic renal cell carcinomas
Parry, L., Maynard, J., Patel, A. S., Clifford, S. C., Morrissey, C. O., Maher, E. R., Cheadle, J. P., & Sampson, J. R. (2001) · British Journal of Cancer · doi:10.1054/bjoc.2001.2072 · Cited by 44 · see citing works
Loss of tuberin, the tuberous‐sclerosis‐complex‐2 gene product is associated with angiogenesis
Nguyen‐Vu, P., Fackler, I., Rust, A., et al. (2001) · Journal of Cutaneous Pathology · doi:10.1034/j.1600-0560.2001.028009470.x · Cited by 38 · see citing works
Momose, S. (2002) · Human Molecular Genetics · doi:10.1093/hmg/11.24.2997 · Cited by 34 · see citing works
Molecular Genetics of Renal Carcinogenesis
Walker, C. L. (1998) · Toxicologic Pathology · doi:10.1177/019262339802600113 · Cited by 31 · see citing works
Maher, E. R. (2013) · Elsevier eBooks · doi:10.1016/b978-0-12-374984-0.01632-6 · Cited by 25 · see citing works
Wang, X., Tokuda, H., Hirade, K., et al. (2002) · Journal of Cellular Biochemistry · doi:10.1002/jcb.10323 · Cited by 17 · see citing works
Fedorov, Y. V., Jones, N. C., & Olwin, B. B. (2002) · Molecular and Cellular Biology · doi:10.1128/mcb.22.4.1140-1149.2002 · Cited by 17 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Motzer, R. J., Escudier, B., Oudard, S., Hutson, T. E., Porta, C., Bracarda, S., Grünwald, V., Thompson, J. A., Figlin, R. A., Hollaender, N., et al. (2008) · The Lancet · doi:10.1016/s0140-6736(08)61039-9 · Cited by 3,019 · see citing works
Activation of a metabolic gene regulatory network downstream of mTOR complex 1
Düvel, K., Yecies, J. L., Menon, S., Raman, P., Lipovsky, A. I., Souza, A. L., Triantafellow, E., Ma, Q., Gorski, R., Cleaver, S., et al. (2010) · Molecular Cell · doi:10.1016/j.molcel.2010.06.022 · Cited by 2,020 · see citing works
The LKB1-AMPK pathway: metabolism and growth control in tumour suppression
Shackelford, D. B., & Shaw, R. J. (2009) · Nature Reviews Cancer · doi:10.1038/nrc2676 · Cited by 1,943 · see citing works
Defining the role of hypoxia-inducible factor 1 in cancer biology and therapeutics
Semenza, G. L. (2010) · Oncogene · doi:10.1038/onc.2009.441 · Cited by 1,712 · see citing works
Normalization of the Vasculature for Treatment of Cancer and Other Diseases
Goel, S., Duda, D. G., Xu, L., Munn, L. L., Boucher, Y., Fukumura, D., & Jain, R. K. (2011) · Physiological Reviews · doi:10.1152/physrev.00038.2010 · Cited by 1,605 · see citing works
Brugarolas, J., Lei, K., Hurley, R. L., Manning, B. D., Reiling, J. H., Hafen, E., Witters, L. A., Ellisen, L. W., & Kaelin, W. G. (2004) · Genes & Development · doi:10.1101/gad.1256804 · Cited by 1,384 · see citing works
Self-citationRankin, E. B., & Giaccia, A. J. (2016) · Science · doi:10.1126/science.aaf4405 · Cited by 1,340 · see citing works
Cellular Adaptation to Hypoxia through Hypoxia Inducible Factors and beyond
Lee, P., Chandel, N. S., & Simon, M. C. (2020) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-020-0227-y · Cited by 1,272 · see citing works
Majumder, P. K., Febbo, P. G., Bikoff, R., Berger, R., Xue, Q., McMahon, L. M., Manola, J., Brugarolas, J., McDonnell, T. J., Golub, T. R., et al. (2004) · Nature Medicine · doi:10.1038/nm1052 · Cited by 964 · see citing works
Self-citationMetformin, independent of AMPK, inhibits mTORC1 in a rag GTPase-dependent manner
Kalender, A., Selvaraj, A., Kim, S. Y., Gulati, P., Brûlé, S., Viollet, B., Kemp, B. E., Bardeesy, N., Dennis, P., Schlager, J. J., et al. (2010) · Cell Metabolism · doi:10.1016/j.cmet.2010.03.014 · Cited by 889 · see citing works
Hypoxia signalling through mTOR and the unfolded protein response in cancer
Wouters, B. G., & Koritzinsky, M. (2008) · Nature Reviews Cancer · doi:10.1038/nrc2501 · Cited by 894 · see citing works
The role of hypoxia-inducible factors in tumorigenesis
Rankin, E. B., & Giaccia, A. J. (2008) · Cell Death & Differentiation · doi:10.1038/cdd.2008.21 · Cited by 806 · see citing works
Sun, Q., Chen, X., Ma, J., Peng, H., Wang, F., Zha, X., Wang, Y., Jing, Y., Yang, H., Chen, R., et al. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1014769108 · Cited by 586 · see citing works
Hypoxia signaling in human health and diseases: implications and prospects for therapeutics
Luo, Z., Tian, M., Yang, G., Tan, Q., Chen, Y., Li, G., Zhang, Q., Li, Y., Wan, P., & Wu, J. (2022) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-022-01080-1 · Cited by 499 · see citing works
Proline hydroxylation and gene expression
Kaelin, W. G. (2005) · Annual Review of Biochemistry · doi:10.1146/annurev.biochem.74.082803.133142 · Cited by 468 · see citing works
Hypoxia. 2. Hypoxia regulates cellular metabolism
Wheaton, W. W., & Chandel, N. S. (2011) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00485.2010 · Cited by 426 · see citing works
The biology of hypoxia: the role of oxygen sensing in development, normal function, and disease
Giaccia, A. J., Simon, M. C., & Johnson, R. (2004) · Genes & Development · doi:10.1101/gad.1243304 · Cited by 380 · see citing works
Regulation of Metabolism by Hypoxia-Inducible Factor 1
Semenza, G. L. (2011) · Cold Spring Harbor Symposia on Quantitative Biology · doi:10.1101/sqb.2011.76.010678 · Cited by 342 · see citing works
The von Hippel-Lindau Tumor Suppressor Protein and Clear Cell Renal Carcinoma
Kaelin, W. G. (2007) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-06-1865 · Cited by 336 · see citing works
Self-citationLoss of the Tumor Suppressor LKB1 Promotes Metabolic Reprogramming of Cancer Cells via HIF-1α
Faubert, B., Vincent, E. E., Griss, T., Samborska, B., Izreig, S., Svensson, R. U., Mamer, O. A., Avizonis, D., Shackelford, D. B., Shaw, R. J., et al. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1312570111 · Cited by 278 · see citing works
Kaelin, W. G. (2011) · Cold Spring Harbor Symposia on Quantitative Biology · doi:10.1101/sqb.2011.76.010975 · Cited by 161 · see citing works
Self-citationThe immunobiology of mTOR in autoimmunity
Suto, T., & Karonitsch, T. (2020) · Journal of Autoimmunity · doi:10.1016/j.jaut.2019.102373 · Cited by 149 · see citing works
Carlson, E. S., Stead, J. D. H., Neal, C. R., Petryk, A., & Georgieff, M. K. (2007) · Hippocampus · doi:10.1002/hipo.20307 · Cited by 141 · see citing works
HIF2α cooperates with RAS to promote lung tumorigenesis in mice
Kim, W. Y., Perera, S., Zhou, B., Carretero, J., Yeh, J. J., Heathcote, S. A., Jackson, A. L., Nikolinakos, P., Ospina, B., Naumov, G., et al. (2009) · Journal of Clinical Investigation · doi:10.1172/jci38443 · Cited by 141 · see citing works
Self-citationGrowth Control Under Stress: mTOR Regulation through the REDD1-TSC Pathway
Ellisen, L. W. (2005) · Cell Cycle · doi:10.4161/cc.4.11.2139 · Cited by 131 · see citing works
Hypoxia and the phenomenon of immune exclusion
Pietrobon, V., & Marincola, F. M. (2021) · Journal of Translational Medicine · doi:10.1186/s12967-020-02667-4 · Cited by 119 · see citing works
Id2 Mediates Tumor Initiation, Proliferation, and Angiogenesis in <i>Rb</i> Mutant Mice
Lasorella, A., Rothschild, G., Yokota, Y., Russell, R. G., & Iavarone, A. (2005) · Molecular and Cellular Biology · doi:10.1128/mcb.25.9.3563-3574.2005 · Cited by 111 · see citing works
Pollard, P., Wortham, N., Barclay, E., Alam, A., Elia, G., Manek, S., Poulsom, R., & Tomlinson, I. (2005) · The Journal of Pathology · doi:10.1002/path.1686 · Cited by 100 · see citing works
Therapeutic Use of mTOR Inhibitors in Renal Diseases: Advances, Drawbacks, and Challenges
Viana, S. D., Reis, F., & Alves, R. (2018) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2018/3693625 · Cited by 48 · see citing works
HIF gene expression in cancer therapy
Chan, D. A., Krieg, A. J., Turcotte, S., & Giaccia, A. J. (2007) · Methods in Enzymology · doi:10.1016/s0076-6879(07)35016-7 · Cited by 26 · see citing works
The TMEM127 human tumor suppressor is a component of the mTORC1 lysosomal nutrient-sensing complex
Deng, Y., Qin, Y., Srikantan, S., Luo, A., Cheng, Z.-M., Flores, S. K., Vogel, K. S., Wang, E., & Dahia, P. L. M. (2018) · Human Molecular Genetics · doi:10.1093/hmg/ddy095 · Cited by 25 · see citing works
- Authors
- Brugarolas, J. B., Vazquez, F., Reddy, A., Sellers, W. R., & Kaelin, W. G.
- Affiliations
- Brigham and Women's Hospital (US)
- Corresponding author
- Kaelin, William G
- Venue
- Cancer Cell
- Publisher
- Elsevier BV
- Published
- 2003-08
- Volume
- 4
- Issue
- 2
- Pages
- 147-158
- ISSN
- 1535-6108 (ISSN-L)
- OpenAlex
- W2062997257
- Cited by
- 528
- References
- 89
- Citations by year
- 2026: 9 · 2025: 6 · 2024: 4 · 2023: 17 · 2022: 12 · 2021: 15 · 2020: 19 · 2019: 17 · 2018: 13 · 2017: 25 · 2016: 22 · 2015: 21 · 2014: 20 · 2013: 29 · 2012: 24
- FWCI
- 17.63
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cancer Cell (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Physiology › Tuberous Sclerosis Complex Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Keywords
- TSC2, tuberous sclerosis complex, vascular endothelial growth factor, mTOR, HIF-1α, hypoxia, rapamycin, trichostatin A, chromatin remodeling, tumor vascularization, tumor suppressor inactivation
- MeSH terms
- Tuberous Sclerosis Complex 2 Protein, Animals, Hypoxia, Cells, Cultured, Gene Expression Regulation, Hydroxamic Acids, Phosphoglycerate Kinase, Phosphopyruvate Hydratase, Protein Kinases, Repressor Proteins, Transcription Factors, Transcription, Genetic, Gene Deletion, Ribosomal Protein S6 Kinases, Sirolimus, Tumor Suppressor Proteins, Excitatory Amino Acid Transporter 2, Vascular Endothelial Growth Factor A, Mice, Hypoxia-Inducible Factor 1, alpha Subunit, TOR Serine-Threonine Kinases
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