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

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:4.6.1.1]

K08042

adenylate cyclase 2 [EC:4.6.1.1]

K08043

adenylate cyclase 3 [EC:4.6.1.1]

K08044

adenylate cyclase 4 [EC:4.6.1.1]

K08045

adenylate cyclase 5 [EC:4.6.1.1]

K08046

adenylate cyclase 6 [EC:4.6.1.1]

K08047

adenylate cyclase 7 [EC:4.6.1.1]

K08048

adenylate cyclase 8 [EC:4.6.1.1]

K08049

adenylate cyclase 9 [EC:4.6.1.1]

K04345

protein kinase A [EC:2.7.11.11]

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:2.1.1.354]

K09187

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

K06622

cyclin-dependent kinase inhibitor 2C

K04685

cyclin-dependent kinase inhibitor 2B

K06621

cyclin-dependent kinase inhibitor 2A

K02089

cyclin-dependent kinase 4 [EC:2.7.11.22]

K02091

cyclin-dependent kinase 6 [EC:2.7.11.22]

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:2.7.11.22]

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:2.7.11.17]

K04353

Ras-related protein Rap-1A

K07836

Ras-related protein Rap-1B

K04365

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

K04368

mitogen-activated protein kinase kinase 1 [EC:2.7.12.2]

K04369

mitogen-activated protein kinase kinase 2 [EC:2.7.12.2]

K04371

mitogen-activated protein kinase 1/3 [EC:2.7.11.24]

K04465

nuclear receptor subfamily 4 group A member 1

K04361

epidermal growth factor receptor [EC:2.7.10.1]

K11839

ubiquitin carboxyl-terminal hydrolase 8 [EC:3.4.19.12]

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:3.1.4.53]

K13298

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

K08560

steroidogenic factor 1

K04684

transcription factor Sp1

K09355

pre-B-cell leukemia transcription factor 1

K00497

steroid 11beta-monooxygenase [EC:1.14.15.4]

K00512

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

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:3.1.4.11]

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:1.14.15.6]

K00070

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

K00513

steroid 21-monooxygenase [EC:1.14.14.16]

K01679

fumarate hydratase, class II [EC:4.2.1.2]

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:2.7.11.26]

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

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