Pathways in clear cell renal cell carcinoma (Homo sapiens)
Inactivation of VHL due to mutation or DNA methylation is an early event in ccRCC that leads to accumulation of the transcription factor HIF-α, which dimerizes with HIF-β and translocates to the nucleus. The resulting HIF-α–HIF-β-induced upregulation of downstream genes promotes cell proliferation, glucose uptake, glycolysis, and angiogenesis.
Mutations in chromatin remodellers and histone modifiers including PBRM1, SETD2, BAP1 and KDM5C lead to global abnormal gene expression patterns, and deficiency in DNA repair, which contributes to genomic instability.
Activation of PI3K–mTOR signalling promotes cell proliferation and tumour aggression, and increases translation of HIF-α, leading to enhanced HIF-α-mediated gene expression. The proposed development pattern of ccRCC is based on tumour evolution analyses and current understanding of genomic variation.
Description adapted from "Precision medicine from the renal cancer genome", Riazalhosseini and Lathrop.
Additional sources of information: mTORC1 complex is based on Wikipedia (https://en.wikipedia.org/wiki/Mechanistic_target_of_rapamycin#mTORC1). PDGFB and TGFB as targets of HIF1A based on KEGG (http://www.genome.jp/kegg-bin/show_pathway?hsa05211).
- Riazalhosseini Y, Lathrop M; ''Precision medicine from the renal cancer genome.''; Nat Rev Nephrol, 2016 PubMed
- Nargund AM, Pham CG, Dong Y, Wang PI, Osmangeyoglu HU, Xie Y, Aras O, Han S, Oyama T, Takeda S, Ray CE, Dong Z, Berge M, Hakimi AA, Monette S, Lekaye CL, Koutcher JA, Leslie CS, Creighton CJ, Weinhold N, Lee W, Tickoo SK, Wang Z, Cheng EH, Hsieh JJ; ''The SWI/SNF Protein PBRM1 Restrains VHL-Loss-Driven Clear Cell Renal Cell Carcinoma.''; Cell Rep, 2017 PubMed
- Dey N, Das F, Mariappan MM, Mandal CC, Ghosh-Choudhury N, Kasinath BS, Choudhury GG; ''MicroRNA-21 orchestrates high glucose-induced signals to TOR complex 1, resulting in renal cell pathology in diabetes.''; J Biol Chem, 2011 PubMed
- Von Roemeling CA, Marlow LA, Radisky DC, Rohl A, Larsen HE, Wei J, Sasinowska H, Zhu H, Drake R, Sasinowski M, Tun HW, Copland JA; ''Functional genomics identifies novel genes essential for clear cell renal cell carcinoma tumor cell proliferation and migration.''; Oncotarget, 2014 PubMed
- Demaria M, Poli V; ''PKM2, STAT3 and HIF-1α: The Warburg's vicious circle.''; JAKSTAT, 2012 PubMed
- Gao X, Wang H, Yang JJ, Liu X, Liu ZR; ''Pyruvate kinase M2 regulates gene transcription by acting as a protein kinase.''; Mol Cell, 2012 PubMed
- ''Comprehensive molecular characterization of clear cell renal cell carcinoma.''; Nature, 2013 PubMed
|97121||view||09:25, 30 April 2018||Khanspers||removed unused anchor|
|97120||view||09:23, 30 April 2018||Khanspers||mutations|
|93145||view||13:21, 31 July 2017||Khanspers||Modified description|
|93144||view||13:13, 31 July 2017||Khanspers||removed extraneous comments on nodes|
|93143||view||13:05, 31 July 2017||Khanspers||updated lit refs, updated details of PBRM1-STAT3 interaction|
|93142||view||12:00, 31 July 2017||Khanspers||added lit refs|
|93141||view||11:28, 31 July 2017||Khanspers||Modified title|
|93140||view||11:27, 31 July 2017||Khanspers||Modified description|
|93139||view||11:12, 31 July 2017||Khanspers||updated mutations, added legend, updated interactions|
|93109||view||11:39, 28 July 2017||AlexanderPico||Ontology Term : 'DOID:4451' removed !|
|93108||view||11:39, 28 July 2017||AlexanderPico||Ontology Term : 'renal clear cell carcinoma' added !|
|93107||view||11:38, 28 July 2017||AlexanderPico||Ontology Term : 'kidney proximal convoluted tubule epithelial cell' added !|
|93106||view||11:37, 28 July 2017||AlexanderPico||Ontology Term : 'kidney cell' added !|
|93105||view||11:23, 28 July 2017||AlexanderPico||Testing new mutation glyphs|
|93104||view||11:16, 28 July 2017||AlexanderPico||Testing mutation state glyphs|
|92883||view||15:30, 13 July 2017||AlexanderPico||Ontology Term : 'signaling pathway' added !|
|92882||view||15:30, 13 July 2017||AlexanderPico||Ontology Term : 'renal carcinoma' added !|
|92881||view||15:29, 13 July 2017||AlexanderPico||Modified title|
|92880||view||15:29, 13 July 2017||AlexanderPico||New pathway|
<cite>No annotated interactions</cite>