KEGG PATHWAY: ko04934

PATHWAY: ko04934

Entry

ko04934                     Pathway

Name

Cushing syndrome

Description

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).

Class

Human Diseases; Endocrine and metabolic disease

Pathway map

ko04934

Cushing syndrome

Disease

H01431

Cushing syndrome

Orthology

K00070

HSD3B; 3beta-hydroxy-Delta5-steroid dehydrogenase / steroid Delta-isomerase [EC:1.1.1.145 5.3.3.1]

K00182

WNT2; wingless-type MMTV integration site family, member 2

K00312

WNT3; wingless-type MMTV integration site family, member 3

K00408

WNT4; wingless-type MMTV integration site family, member 4

K00444

WNT5; wingless-type MMTV integration site family, member 5

K00445

WNT6; wingless-type MMTV integration site family, member 6

K00497

CYP11B1; steroid 11beta-monooxygenase [EC:1.14.15.4]

K00498

CYP11A; cholesterol monooxygenase (side-chain-cleaving) [EC:1.14.15.6]

K00512

CYP17A; steroid 17alpha-monooxygenase / 17alpha-hydroxyprogesterone deacetylase [EC:1.14.14.19 1.14.14.32]

K00513

CYP21A; steroid 21-monooxygenase [EC:1.14.14.16]

K00572

WNT7; wingless-type MMTV integration site family, member 7

K00714

WNT8; wingless-type MMTV integration site family, member 8

K01064

WNT9; wingless-type MMTV integration site family, member 9

K01357

WNT10; wingless-type MMTV integration site family, member 10

K01384

WNT11; wingless-type MMTV integration site family, member 11

K01558

WNT16; wingless-type MMTV integration site family, member 16

K01679

E4.2.1.2B, fumC, FH; fumarate hydratase, class II [EC:4.2.1.2]

K02085

APC; adenomatosis polyposis coli protein

K02089

CDK4; cyclin-dependent kinase 4 [EC:2.7.11.22]

K02091

CDK6; cyclin-dependent kinase 6 [EC:2.7.11.22]

K02105

CTNNB1; catenin beta 1

K02157

AXIN1; axin 1

K02206

CDK2; cyclin-dependent kinase 2 [EC:2.7.11.22]

K02235

FZD2; frizzled 2

K02329

FZD3; frizzled 3

K02353

DVL; segment polarity protein dishevelled

K02354

FZD4, fz4, CD344; frizzled 4

K02375

FZD5_8, fz2; frizzled 5/8

K02376

FZD6; frizzled 6

K02432

FZD1_7, fz; frizzled 1/7

K02620

TCF7, TCF-1; transcription factor 7

K02842

FZD9_10, CD349_50; frizzled 9/10

K03083

GSK3B; glycogen synthase kinase 3 beta [EC:2.7.11.26]

K03209

WNT1; wingless-type MMTV integration site family, member 1

K04166

AGTR1; angiotensin II receptor type 1

K04200

MC2R; melanocortin 2 receptor

K04345

PKA; protein kinase A [EC:2.7.11.11]

K04353

RAP1A; Ras-related protein Rap-1A

K04361

EGFR, ERBB1; epidermal growth factor receptor [EC:2.7.10.1]

K04365

BRAF; B-Raf proto-oncogene serine/threonine-protein kinase [EC:2.7.11.1]

K04368

MAP2K1, MEK1; mitogen-activated protein kinase kinase 1 [EC:2.7.12.2]

K04369

MAP2K2, MEK2; mitogen-activated protein kinase kinase 2 [EC:2.7.12.2]

K04371

ERK, MAPK1_3; mitogen-activated protein kinase 1/3 [EC:2.7.11.24]

K04374

ATF4, CREB2; cyclic AMP-dependent transcription factor ATF-4

K04385

AXIN2; axin 2

K04450

ATF2, CREBP1; cyclic AMP-dependent transcription factor ATF-2

K04465

NR4A1, HMR; nuclear receptor subfamily 4 group A member 1

K04490

TCF7L1; transcription factor 7-like 1

K04491

TCF7L2; transcription factor 7-like 2

K04492

LEF1; lymphoid enhancer-binding factor 1

K04503

CCND1; G1/S-specific cyclin-D1

K04515

CAMK2; calcium/calmodulin-dependent protein kinase (CaM kinase) II [EC:2.7.11.17]

K04578

CRHR1; corticotropin releasing hormone receptor 1

K04579

CRHR2; corticotropin releasing hormone receptor 2

K04630

GNAI; guanine nucleotide-binding protein G(i) subunit alpha

K04632

GNAS; guanine nucleotide-binding protein G(s) subunit alpha

K04634

GNAQ; guanine nucleotide-binding protein G(q) subunit alpha

K04635

GNA11; guanine nucleotide-binding protein subunit alpha-11

K04684

SP1; transcription factor Sp1

K04685

CDKN2B, P15, INK4B; cyclin-dependent kinase inhibitor 2B

K04850

CACNA1C, CAV1.2; voltage-dependent calcium channel L type alpha-1C

K04851

CACNA1D, CAV1.3; voltage-dependent calcium channel L type alpha-1D

K04853

CACNA1F, CAV1.4; voltage-dependent calcium channel L type alpha-1F

K04854

CACNA1G, CAV3.1; voltage-dependent calcium channel T type alpha-1G

K04855

CACNA1H, CAV3.2; voltage-dependent calcium channel T type alpha-1H

K04856

CACNA1I, CAV3.3; voltage-dependent calcium channel T type alpha-1I

K04857

CACNA1S, CAV1.1; voltage-dependent calcium channel L type alpha-1S

K04877

KCNA4, KV1.4; potassium voltage-gated channel Shaker-related subfamily A member 4

K04913

KCNK2, K2P2.1; potassium channel subfamily K member 2

K04914

KCNK3, K2P3.1; potassium channel subfamily K member 3

K04958

ITPR1; inositol 1,4,5-triphosphate receptor type 1

K04959

ITPR2; inositol 1,4,5-triphosphate receptor type 2

K04960

ITPR3; inositol 1,4,5-triphosphate receptor type 3

K05228

POMC; proopiomelanocortin

K05256

CRH; corticotropin-releasing hormone

K05858

PLCB; phosphatidylinositol phospholipase C, beta [EC:3.1.4.11]

K05870

CREB1; cyclic AMP-responsive element-binding protein 1

K06618

RB1; retinoblastoma-associated protein

K06620

E2F3; transcription factor E2F3

K06621

CDKN2A, P16, INK4A; cyclin-dependent kinase inhibitor 2A

K06622

CDKN2C, P18, INK4C; cyclin-dependent kinase inhibitor 2C

K06624

CDKN1B, P27, KIP1; cyclin-dependent kinase inhibitor 1B

K06625

CDKN1A, P21, CIP1; cyclin-dependent kinase inhibitor 1A

K06626

CCNE; G1/S-specific cyclin-E1

K07836

RAP1B; Ras-related protein Rap-1B

K07843

RASD1; RAS, dexamethasone-induced Ras-related protein 1

K08041

ADCY1; adenylate cyclase 1 [EC:4.6.1.1]

K08042

ADCY2; adenylate cyclase 2 [EC:4.6.1.1]

K08043

ADCY3; adenylate cyclase 3 [EC:4.6.1.1]

K08044

ADCY4; adenylate cyclase 4 [EC:4.6.1.1]

K08045

ADCY5; adenylate cyclase 5 [EC:4.6.1.1]

K08046

ADCY6; adenylate cyclase 6 [EC:4.6.1.1]

K08047

ADCY7; adenylate cyclase 7 [EC:4.6.1.1]

K08048

ADCY8; adenylate cyclase 8 [EC:4.6.1.1]

K08049

ADCY9; adenylate cyclase 9 [EC:4.6.1.1]

K08560

NR5A1, SF1; steroidogenic factor 1

K09047

CREB5, CREBPA; cyclic AMP-responsive element-binding protein 5

K09048

CREB3; cyclic AMP-responsive element-binding protein 3

K09049

ATF6B, CREBL1; cyclic AMP-dependent transcription factor ATF-6 beta

K09093

AHR; aryl hydrocarbon receptor

K09097

ARNT; aryl hydrocarbon receptor nuclear translocator

K09186

MLL1; [histone H3]-lysine4 N-trimethyltransferase MLL1 [EC:2.1.1.354]

K09187

MLL2, ALR; [histone H3]-lysine4 N-trimethyltransferase MLL2 [EC:2.1.1.354]

K09355

PBX1; pre-B-cell leukemia transcription factor 1

K09389

E2F2; transcription factor E2F2

K09821

AGT, SERPINA8; angiotensinogen

K11839

USP8, UBP5; ubiquitin carboxyl-terminal hydrolase 8 [EC:3.4.19.12]

K12473

LDLR; low-density lipoprotein receptor

K13298

PDE11; dual 3',5'-cyclic-AMP and -GMP phosphodiesterase 11 [EC:3.1.4.17 3.1.4.35]

K13885

SCARB1; scavenger receptor class B, member 1

K14349

NCEH1, AADACL1; neutral cholesterol ester hydrolase 1 [EC:3.1.1.-]

K14961

RBBP5, SWD1, CPS50; COMPASS component SWD1

K14963

WDR5, SWD3, CPS30; COMPASS component SWD3

K14964

ASH2; Set1/Ash2 histone methyltransferase complex subunit ASH2

K14970

MEN1, MNN1; menin

K16056

ORAI1; calcium release-activated calcium channel protein 1

K16931

STAR; steroidogenic acute regulatory protein, mitochondrial

K17454

E2F1; transcription factor E2F1

K17767

AIP, XAP2; AH receptor-interacting protein

K18437

PDE8; high affinity cAMP-specific and IBMX-insensitive 3',5'-cyclic phosphodiesterase 8 [EC:3.1.4.53]

K22398

MRAP; melanocortin-2 receptor accessory protein

K22499

ARMC5; armadillo repeat-containing protein 5

Compound

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

Reference

PMID:26004339

Authors

Lacroix A, Feelders RA, Stratakis CA, Nieman LK

Title

Cushing's syndrome.

Journal

Lancet 386:913-27 (2015)
DOI:10.1016/S0140-6736(14)61375-1

Reference

PMID:27588171

Authors

Xiong Q, Ge W

Title

Gene mutations in Cushing's disease.

Journal

Biomed Rep 5:277-282 (2016)
DOI:10.3892/br.2016.729

Reference

PMID:25877147

Authors

Fukuoka H, Takahashi Y

Title

The role of genetic and epigenetic changes in pituitary tumorigenesis.

Journal

Neurol Med Chir (Tokyo) 54 Suppl 3:943-57 (2014)
DOI:10.2176/nmc.suppl.2014-3

Reference

PMID:18987159

Authors

Quereda V, Malumbres M

Title

Cell cycle control of pituitary development and disease.

Journal

J Mol Endocrinol 42:75-86 (2009)
DOI:10.1677/JME-08-0146

Reference

PMID:27742789

Authors

Caimari F, Korbonits M

Title

Novel Genetic Causes of Pituitary Adenomas.

Journal

Clin Cancer Res 22:5030-5042 (2016)
DOI:10.1158/1078-0432.CCR-16-0452

Reference

PMID:25350067

Authors

Lecoq AL, Kamenicky P, Guiochon-Mantel A, Chanson P

Title

Genetic mutations in sporadic pituitary adenomas--what to screen for?

Journal

Nat Rev Endocrinol 11:43-54 (2015)
DOI:10.1038/nrendo.2014.181

Reference

PMID:27625633

Authors

Hannah-Shmouni F, Faucz FR, Stratakis CA

Title

Alterations of Phosphodiesterases in Adrenocortical Tumors.

Journal

Front Endocrinol (Lausanne) 7:111 (2016)
DOI:10.3389/fendo.2016.00111

Reference

PMID:21423242

Authors

Melmed S

Title

Pathogenesis of pituitary tumors.

Journal

Nat Rev Endocrinol 7:257-66 (2011)
DOI:10.1038/nrendo.2011.40

Reference

PMID:19407507

Authors

Daly AF, Tichomirowa MA, Beckers A

Title

Genetic, molecular and clinical features of familial isolated pituitary adenomas.

Journal

Horm Res 71 Suppl 2:116-22 (2009)
DOI:10.1159/000192448

Reference

PMID:28850717

Authors

Albani A, Theodoropoulou M, Reincke M

Title

Genetics of Cushing's disease.

Journal

Clin Endocrinol (Oxf) 88:3-12 (2018)
DOI:10.1111/cen.13457

Reference

PMID:26045561

Authors

Duan K, Hernandez KG, Mete O

Title

Clinicopathological correlates of adrenal Cushing's syndrome.

Journal

Postgrad Med J 91:331-42 (2015)
DOI:10.1136/postgradmedj-2014-202612rep

Reference

PMID:26264719

Authors

Drougat L, Espiard S, Bertherat J

Title

Genetics of primary bilateral macronodular adrenal hyperplasia: a model for early diagnosis of Cushing's syndrome?

Journal

Eur J Endocrinol 173:M121-31 (2015)
DOI:10.1530/EJE-15-0532

Reference

PMID:17955016

Authors

Stratakis CA, Boikos SA

Title

Genetics of adrenal tumors associated with Cushing's syndrome: a new classification for bilateral adrenocortical hyperplasias.

Journal

Nat Clin Pract Endocrinol Metab 3:748-57 (2007)
DOI:10.1038/ncpendmet0648

Reference

PMID:19906235

Authors

Refojo D, Holsboer F

Title

CRH signaling. Molecular specificity for drug targeting in the CNS.

Journal

Ann N Y Acad Sci 1179:106-19 (2009)
DOI:10.1111/j.1749-6632.2009.04983.x

Reference

PMID:12089357

Authors

Kovalovsky D, Refojo D, Liberman AC, Hochbaum D, Pereda MP, Coso OA, Stalla GK, Holsboer F, Arzt E

Title

Activation and induction of NUR77/NURR1 in corticotrophs by CRH/cAMP: involvement of calcium, protein kinase A, and MAPK pathways.

Journal

Mol Endocrinol 16:1638-51 (2002)
DOI:10.1210/mend.16.7.0863

Reference

PMID:15380809

Authors

Lacroix A, Baldacchino V, Bourdeau I, Hamet P, Tremblay J

Title

Cushing's syndrome variants secondary to aberrant hormone receptors.

Journal

Trends Endocrinol Metab 15:375-82 (2004)
DOI:10.1016/j.tem.2004.08.007

Reference

PMID:25485838

Authors

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

Title

Mutations in the deubiquitinase gene USP8 cause Cushing's disease.

Journal

Nat Genet 47:31-8 (2015)
DOI:10.1038/ng.3166

Reference

PMID:25930709

Authors

Kaiser UB

Title

Cushing's disease: towards precision medicine.

Journal

Cell Res 25:649-50 (2015)
DOI:10.1038/cr.2015.53

Reference

PMID:28487882

Authors

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

Title

Identification of a novel RASD1 somatic mutation in a USP8-mutated corticotroph adenoma.

Journal

Cold Spring Harb Mol Case Stud 3:a001602 (2017)
DOI:10.1101/mcs.a001602

Reference

PMID:26285834

Authors

Huang C, Shi Y, Zhao Y

Title

USP8 mutation in Cushing's disease.

Journal

Oncotarget 6:18240-1 (2015)
DOI:10.18632/oncotarget.4856