KEGG   PATHWAY: ko04934
ko04934                     Pathway                                

Cushing syndrome
Cushing syndrome (CS) is a rare disorder resulting from prolonged exposure to excess glucocorticoids via exogenous and endogenous sources. The typical clinical features of CS are related to hypercortisolism and include accumulation of central fat, moon facies, neuromuscular weakness, osteoporosis or bone fractures, metabolic complications, and mood changes. Traditionally, endogenous CS is classified as adrenocorticotropic hormone (ACTH)-dependent (about 80%) or ACTH- independent (about 20%). Among ACTH-dependent forms, pituitary corticotroph adenoma (Cushing's disease) is most common. Most pituitary tumors are sporadic, resulting from monoclonal expansion of a single mutated cell. Recently recurrent activating somatic driver mutations in the ubiquitin-specific protease 8 gene (USP8) were identified in almost half of corticotroph adenoma. Germline mutations in MEN1 (encoding menin), AIP (encoding aryl-hydrocarbon receptor-interacting protein), PRKAR1A (encoding cAMP-dependent protein kinase type I alpha regulatory subunit) and CDKN1B (encoding cyclin-dependent kinase inhibitor 1B; also known as p27 Kip1) have been identified in familial forms of pituitary adenomas. However, the frequency of familial pituitary adenomas is less than 5% in patients with pituitary adenomas. Among ACTH-independent CS, adrenal adenoma is most common. Rare adrenal causes of CS include primary bilateral macronodular adrenal hyperplasia (BMAH) or primary pigmented nodular adrenocortical disease (PPNAD).
Human Diseases; Endocrine and metabolic disease
Pathway map
ko04934  Cushing syndrome

H01431  Cushing syndrome
H02049  Bilateral macronodular adrenal hyperplasia
K05256  corticotropin-releasing hormone
K04578  corticotropin releasing hormone receptor 1
K04579  corticotropin releasing hormone receptor 2
K04632  guanine nucleotide-binding protein G(s) subunit alpha
K08041  adenylate cyclase 1 [EC:]
K08042  adenylate cyclase 2 [EC:]
K08043  adenylate cyclase 3 [EC:]
K08044  adenylate cyclase 4 [EC:]
K08045  adenylate cyclase 5 [EC:]
K08046  adenylate cyclase 6 [EC:]
K08047  adenylate cyclase 7 [EC:]
K08048  adenylate cyclase 8 [EC:]
K08049  adenylate cyclase 9 [EC:]
K04345  protein kinase A [EC:]
K05870  cyclic AMP-responsive element-binding protein 1
K04450  cyclic AMP-dependent transcription factor ATF-2
K04374  cyclic AMP-dependent transcription factor ATF-4
K09048  cyclic AMP-responsive element-binding protein 3
K09047  cyclic AMP-responsive element-binding protein 5
K09049  cyclic AMP-dependent transcription factor ATF-6 beta
K14970  menin
K14964  Set1/Ash2 histone methyltransferase complex subunit ASH2
K14961  COMPASS component SWD1
K14963  COMPASS component SWD3
K09186  [histone H3]-lysine4 N-trimethyltransferase MLL1 [EC:]
K09187  [histone H3]-lysine4 N-trimethyltransferase MLL2 [EC:]
K06622  cyclin-dependent kinase inhibitor 2C
K04685  cyclin-dependent kinase inhibitor 2B
K06621  cyclin-dependent kinase inhibitor 2A
K02089  cyclin-dependent kinase 4 [EC:]
K02091  cyclin-dependent kinase 6 [EC:]
K04503  G1/S-specific cyclin-D1
K06618  retinoblastoma-associated protein
K17454  transcription factor E2F1
K09389  transcription factor E2F2
K06620  transcription factor E2F3
K07843  RAS, dexamethasone-induced Ras-related protein 1
K04630  guanine nucleotide-binding protein G(i) subunit alpha
K09093  aryl hydrocarbon receptor
K17767  AH receptor-interacting protein
K09097  aryl hydrocarbon receptor nuclear translocator
K06624  cyclin-dependent kinase inhibitor 1B
K02206  cyclin-dependent kinase 2 [EC:]
K06626  G1/S-specific cyclin-E1
K06625  cyclin-dependent kinase inhibitor 1A
K04850  voltage-dependent calcium channel L type alpha-1C
K04851  voltage-dependent calcium channel L type alpha-1D
K04853  voltage-dependent calcium channel L type alpha-1F
K04857  voltage-dependent calcium channel L type alpha-1S
K04515  calcium/calmodulin-dependent protein kinase (CaM kinase) II [EC:]
K04353  Ras-related protein Rap-1A
K07836  Ras-related protein Rap-1B
K04365  B-Raf proto-oncogene serine/threonine-protein kinase [EC:]
K04368  mitogen-activated protein kinase kinase 1 [EC:]
K04369  mitogen-activated protein kinase kinase 2 [EC:]
K04371  mitogen-activated protein kinase 1/3 [EC:]
K04465  nuclear receptor subfamily 4 group A member 1
K04361  epidermal growth factor receptor [EC:]
K11839  ubiquitin carboxyl-terminal hydrolase 8 [EC:]
K05228  proopiomelanocortin
K04200  melanocortin 2 receptor
K22398  melanocortin 2 receptor accessory protein
K18437  high affinity cAMP-specific and IBMX-insensitive 3',5'-cyclic phosphodiesterase 8 [EC:]
K13298  dual 3',5'-cyclic-AMP and -GMP phosphodiesterase 11 [EC:]
K08560  steroidogenic factor 1
K04684  transcription factor Sp1
K09355  pre-B-cell leukemia transcription factor 1
K00497  steroid 11beta-monooxygenase [EC:]
K00512  steroid 17alpha-monooxygenase / 17alpha-hydroxyprogesterone deacetylase [EC:]
K16931  steroidogenic acute regulatory protein, mitochondrial
K14349  neutral cholesterol ester hydrolase 1 [EC:3.1.1.-]
K22499  armadillo repeat-containing protein 5
K09821  angiotensinogen
K04166  angiotensin II receptor type 1
K04634  guanine nucleotide-binding protein G(q) subunit alpha
K04635  guanine nucleotide-binding protein subunit alpha-11
K05858  phosphatidylinositol phospholipase C, beta [EC:]
K04958  inositol 1,4,5-triphosphate receptor type 1
K04959  inositol 1,4,5-triphosphate receptor type 2
K04960  inositol 1,4,5-triphosphate receptor type 3
K04913  potassium channel subfamily K member 2
K04854  voltage-dependent calcium channel T type alpha-1G
K04855  voltage-dependent calcium channel T type alpha-1H
K04856  voltage-dependent calcium channel T type alpha-1I
K16056  calcium release-activated calcium channel protein 1
K04877  potassium voltage-gated channel Shaker-related subfamily A member 4
K04914  potassium channel subfamily K member 3
K12473  low-density lipoprotein receptor
K13885  scavenger receptor class B, member 1
K00498  cholesterol monooxygenase (side-chain-cleaving) [EC:]
K00070  3beta-hydroxy-Delta5-steroid dehydrogenase / steroid Delta-isomerase [EC:]
K00513  steroid 21-monooxygenase [EC:]
K01679  fumarate hydratase, class II [EC:]
K03209  wingless-type MMTV integration site family, member 1
K00182  wingless-type MMTV integration site family, member 2
K00312  wingless-type MMTV integration site family, member 3
K00408  wingless-type MMTV integration site family, member 4
K00444  wingless-type MMTV integration site family, member 5
K00445  wingless-type MMTV integration site family, member 6
K00572  wingless-type MMTV integration site family, member 7
K00714  wingless-type MMTV integration site family, member 8
K01064  wingless-type MMTV integration site family, member 9
K01357  wingless-type MMTV integration site family, member 10
K01384  wingless-type MMTV integration site family, member 11
K01558  wingless-type MMTV integration site family, member 16
K02432  frizzled 1/7
K02235  frizzled 2
K02329  frizzled 3
K02354  frizzled 4
K02375  frizzled 5/8
K02376  frizzled 6
K02842  frizzled 9/10
K02353  segment polarity protein dishevelled
K03083  glycogen synthase kinase 3 beta [EC:]
K02157  axin 1
K04385  axin 2
K02105  catenin beta 1
K02085  adenomatosis polyposis coli protein
K02620  transcription factor 7
K04490  transcription factor 7-like 1
K04491  transcription factor 7-like 2
K04492  lymphoid enhancer-binding factor 1
C00020  AMP
C00076  Calcium cation
C00187  Cholesterol
C00238  Potassium cation
C00410  Progesterone
C00575  3',5'-Cyclic AMP
C00735  Cortisol
C01176  17alpha-Hydroxyprogesterone
C01245  D-myo-Inositol 1,4,5-trisphosphate
C01953  Pregnenolone
C05138  17alpha-Hydroxypregnenolone
C05488  11-Deoxycortisol
C07557  2,3,7,8-Tetrachlorodibenzodioxin
Lacroix A, Feelders RA, Stratakis CA, Nieman LK
Cushing's syndrome.
Lancet 386:913-27 (2015)
Xiong Q, Ge W
Gene mutations in Cushing's disease.
Biomed Rep 5:277-282 (2016)
Fukuoka H, Takahashi Y
The role of genetic and epigenetic changes in pituitary tumorigenesis.
Neurol Med Chir (Tokyo) 54 Suppl 3:943-57 (2014)
Quereda V, Malumbres M
Cell cycle control of pituitary development and disease.
J Mol Endocrinol 42:75-86 (2009)
Caimari F, Korbonits M
Novel Genetic Causes of Pituitary Adenomas.
Clin Cancer Res 22:5030-5042 (2016)
Lecoq AL, Kamenicky P, Guiochon-Mantel A, Chanson P
Genetic mutations in sporadic pituitary adenomas--what to screen for?
Nat Rev Endocrinol 11:43-54 (2015)
Hannah-Shmouni F, Faucz FR, Stratakis CA
Alterations of Phosphodiesterases in Adrenocortical Tumors.
Front Endocrinol (Lausanne) 7:111 (2016)
Melmed S
Pathogenesis of pituitary tumors.
Nat Rev Endocrinol 7:257-66 (2011)
Daly AF, Tichomirowa MA, Beckers A
Genetic, molecular and clinical features of familial isolated pituitary adenomas.
Horm Res 71 Suppl 2:116-22 (2009)
Albani A, Theodoropoulou M, Reincke M
Genetics of Cushing's disease.
Clin Endocrinol (Oxf) 88:3-12 (2018)
Duan K, Hernandez KG, Mete O
Clinicopathological correlates of adrenal Cushing's syndrome.
Postgrad Med J 91:331-42 (2015)
Drougat L, Espiard S, Bertherat J
Genetics of primary bilateral macronodular adrenal hyperplasia: a model for early diagnosis of Cushing's syndrome?
Eur J Endocrinol 173:M121-31 (2015)
Stratakis CA, Boikos SA
Genetics of adrenal tumors associated with Cushing's syndrome: a new classification for bilateral adrenocortical hyperplasias.
Nat Clin Pract Endocrinol Metab 3:748-57 (2007)
Refojo D, Holsboer F
CRH signaling. Molecular specificity for drug targeting in the CNS.
Ann N Y Acad Sci 1179:106-19 (2009)
Kovalovsky D, Refojo D, Liberman AC, Hochbaum D, Pereda MP, Coso OA, Stalla GK, Holsboer F, Arzt E
Activation and induction of NUR77/NURR1 in corticotrophs by CRH/cAMP: involvement of calcium, protein kinase A, and MAPK pathways.
Mol Endocrinol 16:1638-51 (2002)
Lacroix A, Baldacchino V, Bourdeau I, Hamet P, Tremblay J
Cushing's syndrome variants secondary to aberrant hormone receptors.
Trends Endocrinol Metab 15:375-82 (2004)
Reincke M, Sbiera S, Hayakawa A, Theodoropoulou M, Osswald A, Beuschlein F, Meitinger T, Mizuno-Yamasaki E, Kawaguchi K, Saeki Y, Tanaka K, Wieland T, Graf E, Saeger W, Ronchi CL, Allolio B, Buchfelder M, Strom TM, Fassnacht M, Komada M
Mutations in the deubiquitinase gene USP8 cause Cushing's disease.
Nat Genet 47:31-8 (2015)
Kaiser UB
Cushing's disease: towards precision medicine.
Cell Res 25:649-50 (2015)
Uzilov AV, Cheesman KC, Fink MY, Newman LC, Pandya C, Lalazar Y, Hefti M, Fowkes M, Deikus G, Lau CY, Moe AS, Kinoshita Y, Kasai Y, Zweig M, Gupta A, Starcevic D, Mahajan M, Schadt EE, Post KD, Donovan MJ, Sebra R, Chen R, Geer EB
Identification of a novel RASD1 somatic mutation in a USP8-mutated corticotroph adenoma.
Cold Spring Harb Mol Case Stud 3:a001602 (2017)
Huang C, Shi Y, Zhao Y
USP8 mutation in Cushing's disease.
Oncotarget 6:18240-1 (2015)
Theodoropoulou M, Reincke M, Fassnacht M, Komada M
Decoding the genetic basis of Cushing's disease: USP8 in the spotlight.
Eur J Endocrinol 173:M73-83 (2015)
Yu L, Zhang J, Guo X, Chen X, He Z, He Q
ARMC5 mutations in familial and sporadic primary bilateral macronodular adrenal hyperplasia.
PLoS One 13:e0191602 (2018)
Wu X, Hua X
Menin, histone h3 methyltransferases, and regulation of cell proliferation: current knowledge and perspective.
Curr Mol Med 8:805-15 (2008)
Ozfirat Z, Korbonits M
AIP gene and familial isolated pituitary adenomas.
Mol Cell Endocrinol 326:71-9 (2010)
ko00020  Citrate cycle (TCA cycle)
ko00140  Steroid hormone biosynthesis
ko04020  Calcium signaling pathway
ko04024  cAMP signaling pathway
ko04110  Cell cycle
ko04310  Wnt signaling pathway
ko04927  Cortisol synthesis and secretion
ko04960  Aldosterone-regulated sodium reabsorption

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