KEGG   PATHWAY: rno05211
rno05211                    Pathway                                
Renal cell carcinoma - Rattus norvegicus (rat)
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.
Human Diseases; Cancer: specific types
Pathway map
rno05211  Renal cell carcinoma

Rattus norvegicus (rat) [GN:rno]
29560  Hif1a; hypoxia-inducible factor 1-alpha [KO:K08268]
29452  Epas1; endothelial PAS domain-containing protein 1 [KO:K09095]
54702  Egln3; prolyl hydroxylase EGLN3 [KO:K09592] [EC:]
308457  Egln2; prolyl hydroxylase EGLN2 [KO:K09592] [EC:]
308913  Egln1; egl nine homolog 1 [KO:K09592] [EC:]
24874  Vhl; von Hippel-Lindau disease tumor suppressor [KO:K03871]
64525  Eloc; elongin-C [KO:K03872]
81807  Elob; elongin-B [KO:K03873]
367176  RGD1565653; elongin-B-like isoform X1 [KO:K03873]
300084  Rbx1; E3 ubiquitin-protein ligase RBX1 [KO:K03868] [EC:]
361258  Cul2; cullin-2 [KO:K03870]
25242  Arnt; aryl hydrocarbon receptor nuclear translocator isoform 1 [KO:K09097]
25243  Arnt2; aryl hydrocarbon receptor nuclear translocator 2 [KO:K15589]
54244  Crebbp; histone lysine acetyltransferase CREBBP [KO:K04498] [EC:]
170915  Ep300; LOW QUALITY PROTEIN: histone acetyltransferase p300 [KO:K04498] [EC:]
24778  Slc2a1; solute carrier family 2, facilitated glucose transporter member 1 [KO:K07299]
83785  Vegfa; vascular endothelial growth factor A isoform 6 precursor [KO:K05448]
59086  Tgfb1; transforming growth factor beta-1 proprotein precursor [KO:K13375]
81809  Tgfb2; transforming growth factor beta-2 proprotein precursor [KO:K13376]
25717  Tgfb3; transforming growth factor beta-3 proprotein preproprotein [KO:K13377]
24628  Pdgfb; platelet-derived growth factor subunit B precursor [KO:K17386]
24827  Tgfa; protransforming growth factor alpha preproprotein [KO:K08774]
24446  Hgf; hepatocyte growth factor preproprotein [KO:K05460]
24553  Met; hepatocyte growth factor receptor precursor [KO:K05099] [EC:]
361388  Gab1; GRB2-associated-binding protein 1 [KO:K09593]
85243  Pik3cb; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform [KO:K00922] [EC:]
170911  Pik3ca; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:]
366508  Pik3cd; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform [KO:K00922] [EC:]
25513  Pik3r1; phosphatidylinositol 3-kinase regulatory subunit alpha [KO:K02649]
60664  Pik3r3; phosphatidylinositol 3-kinase regulatory subunit gamma [KO:K02649]
29741  Pik3r2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
24185  Akt1; RAC-alpha serine/threonine-protein kinase [KO:K04456] [EC:]
25233  Akt2; RAC-beta serine/threonine-protein kinase [KO:K04456] [EC:]
29414  Akt3; RAC-gamma serine/threonine-protein kinase [KO:K04456] [EC:]
64639  Bad; bcl2-associated agonist of cell death [KO:K02158]
54245  Crk; adapter molecule crk [KO:K04438]
287942  Crkl; crk-like protein [KO:K04438]
63881  Rapgef1; rap guanine nucleotide exchange factor 1 isoform X19 [KO:K06277]
295347  Rap1a; ras-related protein Rap-1A [KO:K04353]
171337  Rap1b; ras-related protein Rap-1b [KO:K07836]
25622  Ptpn11; tyrosine-protein phosphatase non-receptor type 11 isoform 2 [KO:K07293] [EC:]
81504  Grb2; growth factor receptor-bound protein 2 [KO:K04364]
85384  Sos2; son of sevenless homolog 2 [KO:K03099]
313845  Sos1; son of sevenless homolog 1 [KO:K03099]
293621  Hras; GTPase HRas [KO:K02833]
367858  GTPase HRas [KO:K02833]
24525  Kras; GTPase KRas [KO:K07827]
24605  Nras; GTPase NRas [KO:K07828]
64363  Araf; serine/threonine-protein kinase A-Raf isoform 1 [KO:K08845] [EC:]
114486  Braf; serine/threonine-protein kinase B-raf isoform X6 [KO:K04365] [EC:]
24703  Raf1; RAF proto-oncogene serine/threonine-protein kinase [KO:K04366] [EC:]
170851  Map2k1; dual specificity mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:]
58960  Map2k2; dual specificity mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:]
116590  Mapk1; mitogen-activated protein kinase 1 [KO:K04371] [EC:]
50689  Mapk3; mitogen-activated protein kinase 3 [KO:K04371] [EC:]
24356  Ets1; protein C-ets-1 [KO:K02678]
24516  Jun; transcription factor AP-1 [KO:K04448]
363875  Rac1; ras-related C3 botulinum toxin substrate 1 [KO:K04392]
64465  Cdc42; cell division control protein 42 homolog [KO:K04393]
29431  Pak1; serine/threonine-protein kinase PAK 1 [KO:K04409] [EC:]
29432  Pak2; serine/threonine-protein kinase PAK 2 [KO:K04410] [EC:]
29433  Pak3; serine/threonine-protein kinase PAK 3 [KO:K05733] [EC:]
292756  Pak4; serine/threonine-protein kinase PAK 4 [KO:K05734] [EC:]
311450  Pak5; serine/threonine-protein kinase PAK 5 [KO:K05736] [EC:]
296078  Pak6; serine/threonine-protein kinase PAK 6 [KO:K05735] [EC:]
310687  Prcc; proline-rich protein PRCC [KO:K13105]
317376  Tfe3; transcription factor E3 [KO:K09105]
114851  Cdkn1a; cyclin-dependent kinase inhibitor 1 [KO:K06625]
24368  Fh; fumarate hydratase, mitochondrial precursor [KO:K01679] [EC:]
303185  Flcn; folliculin [KO:K09594]
C00007  Oxygen
C00122  Fumarate
C00149  (S)-Malate
Cohen HT, McGovern FJ.
Renal-cell carcinoma.
N Engl J Med 353:2477-90 (2005)
Pavlovich CP, Schmidt LS.
Searching for the hereditary causes of renal-cell carcinoma.
Nat Rev Cancer 4:381-93 (2004)
Linehan WM, Walther MM, Zbar B.
The genetic basis of cancer of the kidney.
J Urol 170:2163-72 (2003)
Kim WY, Kaelin WG.
Role of VHL gene mutation in human cancer.
J Clin Oncol 22:4991-5004 (2004)
Sudarshan S, Linehan WM, Neckers L.
HIF and fumarate hydratase in renal cancer.
Br J Cancer 96:403-7 (2007)
Sudarshan S, Pinto PA, Neckers L, Linehan WM.
Mechanisms of disease: hereditary leiomyomatosis and renal cell cancer--a distinct form of hereditary kidney cancer.
Nat Clin Pract Urol 4:104-10 (2007)
Birchmeier C, Birchmeier W, Gherardi E, Vande Woude GF.
Met, metastasis, motility and more.
Nat Rev Mol Cell Biol 4:915-25 (2003)
Muller-Hocker J, Babaryka G, Schmid I, Jung A
Overexpression of cyclin D1, D3, and p21 in an infantile renal carcinoma with Xp11.2 TFE3-gene fusion.
Pathol Res Pract 204:589-97 (2008)
Bodmer D, van den Hurk W, van Groningen JJ, Eleveld MJ, Martens GJ, Weterman MA, van Kessel AG.
Understanding familial and non-familial renal cell cancer.
Hum Mol Genet 11:2489-98 (2002)
Kauffman EC, Ricketts CJ, Rais-Bahrami S, Yang Y, Merino MJ, Bottaro DP, Srinivasan R, Linehan WM
Molecular genetics and cellular features of TFE3 and TFEB fusion kidney cancers.
Nat Rev Urol 11:465-75 (2014)
Skalsky YM, Ajuh PM, Parker C, Lamond AI, Goodwin G, Cooper CS
PRCC, the commonest TFE3 fusion partner in papillary renal carcinoma is associated with pre-mRNA splicing factors.
Oncogene 20:178-87 (2001)
Medendorp K, van Groningen JJ, Vreede L, Hetterschijt L, Brugmans L, van den Hurk WH, van Kessel AG
The renal cell carcinoma-associated oncogenic fusion protein PRCCTFE3 provokes p21 WAF1/CIP1-mediated cell cycle delay.
Exp Cell Res 315:2399-409 (2009)
rno00020  Citrate cycle (TCA cycle)
rno04010  MAPK signaling pathway
rno04066  HIF-1 signaling pathway
rno04120  Ubiquitin mediated proteolysis
rno04350  TGF-beta signaling pathway
rno04370  VEGF signaling pathway
KO pathway

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