KEGG   PATHWAY: mcal05211
Entry
mcal05211                   Pathway                                

Name
Renal cell carcinoma - Mus caroli (Ryukyu mouse)
Description
Renal cell cancer (RCC) accounts for ~3% of human malignancies and its incidence appears to be rising. Although most cases of RCC seem to occur sporadically, an inherited predisposition to renal cancer accounts for 1-4% of cases. RCC is not a single disease, it has several morphological subtypes. Conventional RCC (clear cell RCC) accounts for ~80% of cases, followed by papillary RCC (10-15%), chromophobe RCC (5%), and collecting duct RCC (<1%). Genes potentially involved in sporadic neoplasms of each particular type are VHL, MET, BHD, and FH respectively. In the absence of VHL, hypoxia-inducible factor alpha (HIF-alpha) accumulates, leading to production of several growth factors, including vascular endothelial growth factor and platelet-derived growth factor. Activated MET mediates a number of biological effects including motility, invasion of extracellular matrix, cellular transformation, prevention of apoptosis and metastasis formation. Loss of functional FH leads to accumulation of fumarate in the cell, triggering inhibition of HPH and preventing targeted pVHL-mediated degradation of HIF-alpha. BHD mutations cause the Birt-Hogg-Dube syndrome and its associated chromophobe, hybrid oncocytic, and conventional (clear cell) RCC.
Class
Human Diseases; Cancer: specific types
Pathway map
mcal05211  Renal cell carcinoma
mcal05211

Organism
Mus caroli (Ryukyu mouse) [GN:mcal]
Gene
110306746  Hif1a; hypoxia-inducible factor 1-alpha isoform X1 [KO:K08268]
110312404  Epas1; endothelial PAS domain-containing protein 1 [KO:K09095]
110299462  Egln2; egl nine homolog 2 [KO:K09592] [EC:1.14.11.29]
110307114  Egln3; egl nine homolog 3 isoform X1 [KO:K09592] [EC:1.14.11.29]
110300648  Egln1; egl nine homolog 1 [KO:K09592] [EC:1.14.11.29]
110296136  Vhl; von Hippel-Lindau disease tumor suppressor [KO:K03871]
110292603  Eloc; elongin-C [KO:K03872]
110302142  elongin-B [KO:K03873]
110283766  Elob; elongin-B [KO:K03873]
110310464  Rbx1; E3 ubiquitin-protein ligase RBX1 [KO:K03868] [EC:2.3.2.32]
110284468  Cul2; cullin-2 isoform X1 [KO:K03870]
110290783  Arnt; aryl hydrocarbon receptor nuclear translocator isoform X1 [KO:K09097]
110298280  Arnt2; aryl hydrocarbon receptor nuclear translocator 2 [KO:K15589]
110310313  Ep300; LOW QUALITY PROTEIN: histone acetyltransferase p300 [KO:K04498] [EC:2.3.1.48]
110311224  Crebbp; CREB-binding protein [KO:K04498] [EC:2.3.1.48]
110292203  Slc2a1; solute carrier family 2, facilitated glucose transporter member 1 [KO:K07299]
110284402  Vegfa; vascular endothelial growth factor A isoform X1 [KO:K05448]
110298438  Tgfb1; transforming growth factor beta-1 [KO:K13375]
110292955  Tgfb2; transforming growth factor beta-2 isoform X1 [KO:K13376]
110306834  Tgfb3; transforming growth factor beta-3 [KO:K13377]
110310626  Pdgfb; platelet-derived growth factor subunit B [KO:K17386]
110295684  Tgfa; protransforming growth factor alpha [KO:K08774]
110294216  Hgf; hepatocyte growth factor isoform X1 [KO:K05460]
110295947  Met; hepatocyte growth factor receptor isoform X1 [KO:K05099] [EC:2.7.10.1]
110300068  Gab1; GRB2-associated-binding protein 1 [KO:K09593]
110290798  Pik3ca; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
110292183  Pik3cd; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
110301355  Pik3cb; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform [KO:K00922] [EC:2.7.1.153]
110308009  Pik3r1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649]
110299855  Pik3r2; phosphatidylinositol 3-kinase regulatory subunit beta isoform X1 [KO:K02649]
110292624  phosphatidylinositol 3-kinase regulatory subunit gamma isoform X1 [KO:K02649]
110297609  Akt2; RAC-beta serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
110294471  Akt3; RAC-gamma serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
110307022  Akt1; RAC-alpha serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
110285481  Bad; bcl2-associated agonist of cell death isoform X1 [KO:K02158]
110305233  Crk; adapter molecule crk isoform X1 [KO:K04438]
110311596  Crkl; crk-like protein [KO:K04438]
110309132  Rapgef1; rap guanine nucleotide exchange factor 1 isoform X1 [KO:K06277]
110290796  Rap1a; ras-related protein Rap-1A [KO:K04353]
110303320  Rap1b; ras-related protein Rap-1b [KO:K07836]
110294055  Ptpn11; tyrosine-protein phosphatase non-receptor type 11 isoform X1 [KO:K07293] [EC:3.1.3.48]
110304772  Grb2; growth factor receptor-bound protein 2 [KO:K04364]
110306968  Sos2; son of sevenless homolog 2 [KO:K03099]
110312423  Sos1; son of sevenless homolog 1 [KO:K03099]
110297313  Hras; GTPase HRas isoform X1 [KO:K02833]
110296194  Kras; GTPase KRas isoform X1 [KO:K07827]
110290873  Nras; GTPase NRas [KO:K07828]
110287540  Araf; serine/threonine-protein kinase A-Raf isoform X1 [KO:K08845] [EC:2.7.11.1]
110295945  Braf; serine/threonine-protein kinase B-raf isoform X1 [KO:K04365] [EC:2.7.11.1]
110296919  Raf1; RAF proto-oncogene serine/threonine-protein kinase [KO:K04366] [EC:2.7.11.1]
110301502  Map2k1; dual specificity mitogen-activated protein kinase kinase 1 isoform X1 [KO:K04368] [EC:2.7.12.2]
110303196  Map2k2; dual specificity mitogen-activated protein kinase kinase 2 isoform X1 [KO:K04369] [EC:2.7.12.2]
110297836  Mapk3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
110311382  Mapk1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
110301829  Ets1; protein C-ets-1 [KO:K02678]
110292423  Jun; transcription factor AP-1 [KO:K04448]
110293965  Rac1; ras-related C3 botulinum toxin substrate 1 [KO:K04392]
110292517  Cdc42; cell division control protein 42 homolog isoform X1 [KO:K04393]
110298300  Pak1; serine/threonine-protein kinase PAK 1 [KO:K04409] [EC:2.7.11.1]
110311434  Pak2; serine/threonine-protein kinase PAK 2 [KO:K04410] [EC:2.7.11.1]
110286479  Pak3; serine/threonine-protein kinase PAK 3 isoform X1 [KO:K05733] [EC:2.7.11.1]
110297818  Pak4; serine/threonine-protein kinase PAK 4 [KO:K05734] [EC:2.7.11.1]
110289454  Pak5; serine/threonine-protein kinase PAK 5 [KO:K05736] [EC:2.7.11.1]
110288173  serine/threonine-protein kinase PAK 6 [KO:K05735] [EC:2.7.11.1]
110291859  Prcc; proline-rich protein PRCC [KO:K13105]
110286603  Tfe3; transcription factor E3 isoform X1 [KO:K09105]
110283679  Cdkn1a; cyclin-dependent kinase inhibitor 1 [KO:K06625]
110290800  Fh; fumarate hydratase, mitochondrial [KO:K01679] [EC:4.2.1.2]
110305887  Flcn; LOW QUALITY PROTEIN: folliculin [KO:K09594]
Compound
C00007  Oxygen
C00122  Fumarate
C00149  (S)-Malate
Reference
  Authors
Cohen HT, McGovern FJ.
  Title
Renal-cell carcinoma.
  Journal
N Engl J Med 353:2477-90 (2005)
DOI:10.1056/NEJMra043172
Reference
  Authors
Pavlovich CP, Schmidt LS.
  Title
Searching for the hereditary causes of renal-cell carcinoma.
  Journal
Nat Rev Cancer 4:381-93 (2004)
DOI:10.1038/nrc1364
Reference
  Authors
Linehan WM, Walther MM, Zbar B.
  Title
The genetic basis of cancer of the kidney.
  Journal
J Urol 170:2163-72 (2003)
DOI:10.1097/01.ju.0000096060.92397.ed
Reference
  Authors
Kim WY, Kaelin WG.
  Title
Role of VHL gene mutation in human cancer.
  Journal
J Clin Oncol 22:4991-5004 (2004)
DOI:10.1200/JCO.2004.05.061
Reference
  Authors
Sudarshan S, Linehan WM, Neckers L.
  Title
HIF and fumarate hydratase in renal cancer.
  Journal
Br J Cancer 96:403-7 (2007)
DOI:10.1038/sj.bjc.6603547
Reference
  Authors
Sudarshan S, Pinto PA, Neckers L, Linehan WM.
  Title
Mechanisms of disease: hereditary leiomyomatosis and renal cell cancer--a distinct form of hereditary kidney cancer.
  Journal
Nat Clin Pract Urol 4:104-10 (2007)
DOI:10.1038/ncpuro0711
Reference
  Authors
Birchmeier C, Birchmeier W, Gherardi E, Vande Woude GF.
  Title
Met, metastasis, motility and more.
  Journal
Nat Rev Mol Cell Biol 4:915-25 (2003)
DOI:10.1038/nrm1261
Reference
  Authors
Muller-Hocker J, Babaryka G, Schmid I, Jung A
  Title
Overexpression of cyclin D1, D3, and p21 in an infantile renal carcinoma with Xp11.2 TFE3-gene fusion.
  Journal
Pathol Res Pract 204:589-97 (2008)
DOI:10.1016/j.prp.2008.01.010
Reference
  Authors
Bodmer D, van den Hurk W, van Groningen JJ, Eleveld MJ, Martens GJ, Weterman MA, van Kessel AG.
  Title
Understanding familial and non-familial renal cell cancer.
  Journal
Hum Mol Genet 11:2489-98 (2002)
DOI:10.1093/hmg/11.20.2489
Reference
  Authors
Kauffman EC, Ricketts CJ, Rais-Bahrami S, Yang Y, Merino MJ, Bottaro DP, Srinivasan R, Linehan WM
  Title
Molecular genetics and cellular features of TFE3 and TFEB fusion kidney cancers.
  Journal
Nat Rev Urol 11:465-75 (2014)
DOI:10.1038/nrurol.2014.162
Reference
  Authors
Skalsky YM, Ajuh PM, Parker C, Lamond AI, Goodwin G, Cooper CS
  Title
PRCC, the commonest TFE3 fusion partner in papillary renal carcinoma is associated with pre-mRNA splicing factors.
  Journal
Oncogene 20:178-87 (2001)
DOI:10.1038/sj.onc.1204056
Reference
  Authors
Medendorp K, van Groningen JJ, Vreede L, Hetterschijt L, Brugmans L, van den Hurk WH, van Kessel AG
  Title
The renal cell carcinoma-associated oncogenic fusion protein PRCCTFE3 provokes p21 WAF1/CIP1-mediated cell cycle delay.
  Journal
Exp Cell Res 315:2399-409 (2009)
DOI:10.1016/j.yexcr.2009.04.022
Related
pathway
mcal00020  Citrate cycle (TCA cycle)
mcal04010  MAPK signaling pathway
mcal04066  HIF-1 signaling pathway
mcal04120  Ubiquitin mediated proteolysis
mcal04350  TGF-beta signaling pathway
mcal04370  VEGF signaling pathway
KO pathway
ko05211   
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