Human Disease Model Report: cancer, multiple, Hedgehog signaling pathway

General Information

Name

cancer, multiple, Hedgehog signaling pathway

FlyBase ID

FBhh0001573

Disease Ontology Term

cancer

Parent Disease

OMIM

Overview

Using an eye-growth phenotype in adult Drosophila, mechanisms of tumorigenesis involving the Hedgehog signaling pathway have been investigated. The Drosophila genes ci (orthologous to human GLI3, GLI2, and GLI1) and rdx (also called hib; orthologous to human SPOP and SPOPL) have been characterized in the context of this disease model.

Neither knockdown of rdx alone nor overexpression of activated ci alone is sufficient to generate tumor-like eye phenotype; however, ci overexpression combined with RNAi-mediated loss of function of rdx causes a tumor-like big eye phenotype manifested by enlarged and protruding eyes.

Functional complementation in this system has been demonstrated using the mouse SPOP and GLI2 orthologs. Overexpression of Mmus\Gli2 can replace overexpression of ci, causing an enlarged eye phenotype in combination with rdx RNAi. Using the mouse ortholog of SPOP, Mmus\Spop, overexpression of this transgene in addition to activated ci and rdx RNAi rescues the tumor-like eye phenotype. Variants of SPOP implicated in the development of cancer fail to rescue in this assay; see the 'Disease-Implicated Variants' table below.

For more information on the canonical Hedgehog signaling pathway in Drosophila, see related pathway reports (FBgg0000978 and component group reports).

See also the human disease models 'basal cell carcinoma, SMO-related' (FBhh0001201) and 'cancer, epithelial, Notch signaling, Hedgehog signaling' (FBhh0001075).

[updated May 2024 by FlyBase; FBrf0222196]

Disease Summary Information

Disease Summary: cancer, multiple, Hedgehog signaling pathway

OMIM report

Human gene(s) implicated

Symptoms and phenotype

Genetics

The Hedgehog signaling pathway is a driver of several cancer subtypes; in addition, the pathway is aberrantly activated in a wide range of malignancies in response to therapy (reviewed in Miller et al, 2023; pubmed:37954979).

(FlyBase Curators, 2013-)

Several cancers including non-small cell lung cancers (NSCLC), gliomas, and breast carcinomas upregulate Hh signaling, thereby resisting cell cycle arrest; mutations in the pathway are associated with a hereditary form of basal cell carcinoma (BCC)(reviewed in Miller et al, 2023; pubmed:37954979).

(FlyBase Curators, 2013-)

Cellular phenotype and pathology

Molecular information

External links

COSMIC gene: SPOP
COSMIC gene: GLI3
COSMIC gene: GLI2
COSMIC gene: GLI1
Gene2Function (human gene): GLI3
Gene2Function (human gene): GLI1
Gene2Function (human gene): SPOP
Gene2Function (human gene): GLI2
Gene Cards: GLI3
Gene Cards: GLI1
Gene Cards: SPOP
Gene Cards: GLI2
MedlinePlus (gene): GLI3
MedlinePlus (gene): GLI1
MedlinePlus (gene): SPOP
MedlinePlus (gene): GLI2
KEGG Disease Pathways: Pathways in Cancer
MARRVEL (human gene): GLI3
MARRVEL (human gene): GLI1
MARRVEL (human gene): SPOP
MARRVEL (human gene): GLI2
NCBI (Entrez) gene: GLI3; GLI family zinc finger 3
NCBI (Entrez) gene: GLI1; GLI family zinc finger 1
NCBI (Entrez) gene: SPOP; speckle type BTB/POZ protein
NCBI (Entrez) gene: GLI2; GLI family zinc finger 2

Disease synonyms

Related Diseases

Related human health report(s)

basal cell carcinoma, SMO-related

cancer, epithelial, Notch signaling, Hedgehog signaling

Ortholog Information

Human gene(s) in FlyBase

Human gene (HGNC)

Symbol / Name

GLI1; GLI family zinc finger 1

D. melanogaster ortholog (based on DIOPT)

Dmel\ci

(DIOPT, 2013-)

Comments on ortholog(s)

Many to one: 3 human genes to 1 Drosophila gene.

Human gene (HGNC)

Symbol / Name

SPOP; speckle type BTB/POZ protein

D. melanogaster ortholog (based on DIOPT)

Dmel\rdx

(DIOPT, 2013-)

Comments on ortholog(s)

Many to one: 2 human genes to 1 Drosophila gene.

Human gene (HGNC)

Symbol / Name

GLI3; GLI family zinc finger 3

D. melanogaster ortholog (based on DIOPT)

Dmel\ci

(DIOPT, 2013-)

Comments on ortholog(s)

Many to one: 3 human genes to 1 Drosophila gene.

Human gene (HGNC)

Symbol / Name

GLI2; GLI family zinc finger 2

D. melanogaster ortholog (based on DIOPT)

Dmel\ci

(DIOPT, 2013-)

Comments on ortholog(s)

Many to one: 3 human genes to 1 Drosophila gene.

Other mammalian ortholog(s) used

D. melanogaster Gene Information (2)

Dmel\ci

Gene Snapshot

cubitus interruptus (ci) encodes a Zn-finger family of transcription factor. It contributes to Hedgehog (Hh) signaling pathway that is involved in pattern formation and growth control. The product of ci undergoes limited proteolysis to be converted into a truncated form that function as a transcription repressor in the absence of the ligand encoded by hh but is converted into a full-length transcription activator in the presence of the product of hh. [Date last reviewed: 2019-03-07]

Molecular function (GO)

Cellular component (GO)

Gene Groups / Pathways

Comments on ortholog(s)

High-scoring ortholog of human GLI3 and GLI2; moderate-scoring ortholog of GLI1 (3 human to 1 Drosophila).

Orthologs and Alignments from DRSC

DIOPT - DRSC Integrative Ortholog Prediction Tool - Click the link below to search for orthologs in Humans

H. sapiens (Human)

Dmel\rdx

Gene Snapshot

roadkill (rdx) encodes a protein that functions as a substrate recognition component of Cul3-based E3 ubiquitin ligase complexes. It regulates the Hedgehog signaling pathway by promoting the degradation of the transcription factor encoded by ci. [Date last reviewed: 2019-03-14]

Molecular function (GO)

Cellular component (GO)

Gene Groups / Pathways

HH-SMON

Comments on ortholog(s)

Moderate- to high-scoring ortholog of human SPOP and SPOPL (2 human to 1 Drosophila).

Orthologs and Alignments from DRSC

DIOPT - DRSC Integrative Ortholog Prediction Tool - Click the link below to search for orthologs in Humans

H. sapiens (Human)

Other Genes Used: Viral, Bacterial, Synthetic (0)

Summary of Physical Interactions (59 groups)

protein-protein

Interacting group

Assay

References

anti tag coimmunoprecipitation, anti tag western blot, fluorescent resonance energy transfer, fluorescence microscopy

(Zhang et al., 2009)

ci - Ada2b

anti tag coimmunoprecipitation, peptide massfingerprinting

(Weake et al., 2011)

ci - bur

anti tag coimmunoprecipitation, anti tag western blot

(Zhou et al., 2015)

ci - CkIα

anti tag coimmunoprecipitation, anti tag western blot

(Shi et al., 2011, Zhang et al., 2005)

ci - cos

pull down, autoradiography, anti bait coimmunoprecipitation, western blot, anti tag coimmunoprecipitation, anti tag western blot, two hybrid, colocalization, fluorescence microscopy, inferred by author, molecular sieving, peptide massfingerprinting

(Li et al., 2020, Oh et al., 2015, Zhou et al., 2015, Ranieri et al., 2012, Shi et al., 2011, Zhou and Kalderon, 2010, Farzan et al., 2009, Ruel et al., 2007, Zhang et al., 2005, Stegman et al., 2004, Wang and Jiang, 2004, Lum et al., 2003, Ruel et al., 2003, Monnier et al., 2002, Stegman et al., 2000, Wang et al., 2000, Robbins et al., 1997, Sisson et al., 1997)

ci - croc

anti tag coimmunoprecipitation, anti tag western blot

(Tu et al., 2020)

ci - Cul1

enzymatic study, peptide massfingerprinting, pull down, anti tag western blot

(Zhang et al., 2013, Smelkinson et al., 2007)

ci - Cul3

enzymatic study, peptide massfingerprinting

(Zhang et al., 2013)

ci - dbr

two hybrid, pull down, autoradiography, anti bait coimmunoprecipitation, anti tag western blot, anti tag coimmunoprecipitation

(Dai et al., 2003)

ci - dco

enzymatic study, autoradiography, interologs mapping, inferred by curator

(Shi et al., 2014)

ci - eff

enzymatic study, western blot

(Pan et al., 2017)

ci - fu

protein three hybrid, anti bait coimmunoprecipitation, western blot, enzymatic study, molecular sieving, anti tag coimmunoprecipitation, anti tag western blot, two hybrid

(Zhou et al., 2022, Han et al., 2019, Farzan et al., 2009, Paces-Fessy et al., 2004, Stegman et al., 2004, Wang and Jiang, 2004, Horabin et al., 2003, Stegman et al., 2000, Monnier et al., 1998, Robbins et al., 1997)

ci - Gug

pull down, anti tag western blot, anti tag coimmunoprecipitation, two hybrid

(Zhang et al., 2013)

ci - HDAC1

anti tag coimmunoprecipitation, anti tag western blot

(Zhang et al., 2013)

ci - hpo

anti tag coimmunoprecipitation, anti tag western blot

(Li et al., 2015)

ci - hyd

coimmunoprecipitation, western blot

(Moncrieff et al., 2015)

ci - hyx

pull down, autoradiography

(Mosimann et al., 2009)

ci - Kap-α3

anti tag coimmunoprecipitation, anti tag western blot, two hybrid

(Seong et al., 2010)

ci - kto

anti tag coimmunoprecipitation, anti tag western blot

(Mao et al., 2014)

ci - lwr

pull down, western blot

(Lv et al., 2016)

ci - mts

anti tag coimmunoprecipitation, western blot

(Su et al., 2011)

ci - nej

anti tag coimmunoprecipitation, anti tag western blot, two hybrid, lambda phage display, pull down, molecular weight estimation by staining

(Han et al., 2019, Han et al., 2015, Chen et al., 2000, Akimaru et al., 1997)

ci - Npl4

pull down, western blot

(Zhang et al., 2013)

ci - Pka-C1

anti tag coimmunoprecipitation, anti tag western blot, bimolecular fluorescence complementation, fluorescence microscopy

(Ranieri et al., 2014)

ci - Polr2C

anti tag coimmunoprecipitation, anti tag western blot

(Gao et al., 2023)

ci - Polr2G

anti tag coimmunoprecipitation, anti tag western blot

(Gao et al., 2023)

ci - ptc

anti bait coimmunoprecipitation, western blot

(Walthall et al., 2007)

ci - Rack1

anti tag coimmunoprecipitation, anti tag western blot

(Li et al., 2020)

ci - Rbfox1

anti tag coimmunoprecipitation, western blot, anti bait coimmunoprecipitation, anti tag western blot, pull down

(Usha and Shashidhara, 2010)

ci - rdx

two hybrid, pull down, western blot, anti tag coimmunoprecipitation, anti tag western blot, enzymatic study, peptide massfingerprinting

(Han et al., 2019, Zhou et al., 2015, Liu et al., 2014, Shi et al., 2014, Zhang et al., 2013, Seong et al., 2010, Zhang et al., 2009, Kent et al., 2006, Zhang et al., 2006)

ci - sgg

anti tag coimmunoprecipitation, anti tag western blot

(Shi et al., 2011, Zhang et al., 2005)

ci - skd

anti tag coimmunoprecipitation, anti tag western blot

(Mao et al., 2014)

ci - SkpA

pull down, anti tag western blot

(Smelkinson et al., 2007)

ci - slmb

pull down, anti tag western blot, enzymatic study, peptide massfingerprinting, autoradiography

(Zhang et al., 2013, Smelkinson et al., 2007, Smelkinson and Kalderon, 2006, Jia et al., 2005, Dai et al., 2003)

ci - smo

anti bait coimmunoprecipitation, western blot, peptide massfingerprinting

(Walthall et al., 2007, Lum et al., 2003, Ruel et al., 2003)

ci - sqh

anti tag coimmunoprecipitation, anti tag western blot, pull down, Identification by mass spectrometry

(Liu et al., 2015)

ci - Stat92E

anti tag coimmunoprecipitation, anti tag western blot

(Liu et al., 2015)

ci - Su(fu)

fluorescent resonance energy transfer, fluorescence microscopy, pull down, autoradiography, western blot, two hybrid, molecular sieving, anti bait coimmunoprecipitation, anti tag coimmunoprecipitation, anti tag western blot, isothermal titration calorimetry, predetermined participant

(Zhou et al., 2022, Han et al., 2019, Han et al., 2015, Oh et al., 2015, Zhou et al., 2015, Shi et al., 2014, Zhang et al., 2013, Shi et al., 2011, Farzan et al., 2009, Zhang et al., 2006, Paces-Fessy et al., 2004, Wang and Jiang, 2004, Lum et al., 2003, Methot and Basler, 2000, Stegman et al., 2000, Monnier et al., 1998, Paumard-Rigal et al., 1998)

ci - Sumo

pull down, western blot

(Lv et al., 2016)

ci - Sxl

anti bait coimmunoprecipitation, western blot

(Walthall et al., 2007, Horabin et al., 2003)

ci - tai

anti tag coimmunoprecipitation, anti tag western blot, electrophoretic mobility shift assay

(Yu et al., 2024)

ci - Tnpo

anti tag coimmunoprecipitation, anti tag western blot, pull down

(Han et al., 2019, Shi et al., 2014)

ci - tws

anti tag coimmunoprecipitation, western blot

(Su et al., 2011)

ci - Usp7

anti tag coimmunoprecipitation, anti tag western blot, pull down

(Sun et al., 2019, Zhou et al., 2015)

ci - yki

anti tag coimmunoprecipitation, anti tag western blot

(Li et al., 2015)

rdx

protein-protein

Interacting group

Assay

References

rdx

anti tag coimmunoprecipitation, anti tag western blot

(Zhou et al., 2015, Zhang et al., 2009)

rdx - cal1

two hybrid, anti tag coimmunoprecipitation, western blot

(Bade et al., 2014)

rdx - Cand1

pull down, western blot

(Kim et al., 2010)

rdx - CG8833

anti tag coimmunoprecipitation, peptide massfingerprinting, experimental knowledge based

(Rhee et al., 2014)

rdx - CG14074

two hybrid

(Hu et al., 2017.6.13)

rdx - ci

two hybrid, pull down, western blot, anti tag coimmunoprecipitation, anti tag western blot, enzymatic study, peptide massfingerprinting

(Han et al., 2019, Zhou et al., 2015, Liu et al., 2014, Shi et al., 2014, Zhang et al., 2013, Seong et al., 2010, Zhang et al., 2009, Kent et al., 2006, Zhang et al., 2006)

rdx - COX5B

anti tag coimmunoprecipitation, peptide massfingerprinting, experimental knowledge based

(Rhee et al., 2014)

rdx - Cul3

anti tag coimmunoprecipitation, anti tag western blot, two hybrid, pull down, autoradiography, western blot

(Zhou et al., 2015, Zhang et al., 2013, Kim et al., 2010, Arama et al., 2007, Zhang et al., 2006)

rdx - Diap1

anti tag coimmunoprecipitation, anti tag western blot

(Liu et al., 2021)

rdx - lwr

two hybrid

(Hu et al., 2017.6.13)

rdx - Pc

pull down, peptide massfingerprinting

(Strübbe et al., 2011)

rdx - puc

anti tag coimmunoprecipitation, anti tag western blot, pull down, western blot

(Liu et al., 2009, Zhang et al., 2009, Zhuang et al., 2009)

rdx - RanBP3

two hybrid

(Hu et al., 2017.6.13)

rdx - Ubi-p5E

anti tag coimmunoprecipitation, anti tag western blot

(Zhou et al., 2015)

rdx - Ubi-p63E

anti tag coimmunoprecipitation, anti tag western blot

(Zhou et al., 2015)

Alleles Reported to Model Human Disease (Disease Ontology) (7 alleles)

Mmus\Spop

Models Based on Experimental Evidence ( 0 )

Allele

Disease

Evidence

References

Modifiers Based on Experimental Evidence ( 1 )

Allele

Disease

Interaction

References

Mmus\Spop^UAS.Tag:FLAG

ameliorates cancer

modeled by ci^{-3P.UAS.W.Tag:HA}, rdx^NIG.9924R

(Gao et al., 2023)

modeled by Mmus\Gli2^UAS.Tag:MYC, ci^{-3P.UAS.W.Tag:HA}

(Gao et al., 2023)

Mmus\Gli2

Models Based on Experimental Evidence ( 1 )

Allele

Disease

Evidence

References

Mmus\Gli2^UAS.Tag:MYC

model of cancer

CEA with ci^{-3P.UAS.W.Tag:HA}

(Gao et al., 2023)

Modifiers Based on Experimental Evidence ( 0 )

Allele

Disease

Interaction

References

Models Based on Experimental Evidence ( 2 )

Allele

Disease

Evidence

References

ci^{-3P.UAS.W.Tag:HA}

model of cancer

CEA with rdx^NIG.9924R

(Gao et al., 2023)

CEA with Mmus\Gli2^UAS.Tag:MYC

(Gao et al., 2023)

ci^RNAi.UAS.cUa

model of primary bacterial infectious disease

CEA

(Lee et al., 2015)

Modifiers Based on Experimental Evidence ( 3 )

Allele

Disease

Interaction

References

ci^5m.UAS

exacerbates cancer

modeled by Hipk^UAS.Tag:HA

(Blaquiere et al., 2018)

ci^76.UAS

DOES NOT ameliorate cancer

modeled by Hipk^UAS.Tag:HA

(Blaquiere et al., 2018)

ci^RNAi.UAS.cUa

ameliorates atypical teratoid rhabdoid tumor

modeled by Snr1^RNAi.UAS.cUa

(Jeibmann et al., 2014)

rdx

Models Based on Experimental Evidence ( 1 )

Allele

Disease

Evidence

References

rdx^NIG.9924R

model of cancer

CEA with ci^{-3P.UAS.W.Tag:HA}

(Gao et al., 2023)

Modifiers Based on Experimental Evidence ( 0 )

Allele

Disease

Interaction

References

Alleles Representing Disease-Implicated Variants

Genetic Tools, Stocks and Reagents

Sources of Stocks

Contact lab of origin for a reagent not available from a public stock center.

Bloomington Stock Center Disease Page

Related mammalian, viral, bacterial, or synthetic transgenes

Allele

Transgene

Publicly Available Stocks

Hsap\GLI1^{UAS.Tag:MYC,Tag:HA}

P{UAS-Hsap\GLI}

Hsap\GLI1^{αTub84B.Tag:MYC,Tag:HA}

P{alphaTub84B-Hsap\GLI}

Hsap\GLI1^Δ1-130.UAS

P{UAS-hGli1Delta1-130}

Hsap\GLI1^SYGH.UAS

P{UAS-hGli1DeltaSYGH}

P{UAS-hGli1DeltaCORD}

Hsap\GLI1^S463A.UAS

P{UAS-hGli1.S463A}

Hsap\GLI1^{Δ1-524.ci.1-829.UAS}

P{UAS-ci-hGli1.M}

Hsap\GLI3^UAS.Tag:HA

PBac{UAS-hGLI3.HA}

w¹¹¹⁸; PBac{UAS-hGLI3.HA}VK00037

Hsap\GLI3^{UAS.Tag:MYC,Tag:HA}

P{UAS-Hsap\GLI3}

Hsap\GLI3^{αTub84B.Tag:MYC,Tag:HA}

P{alphaTub84B-Hsap\GLI3}

Hsap\GLI3^UAS.Tag:MYC

P{UAS-Myc-Hsap\GLI3}

Mmus\Spop^{ΔMATH.UAS.Tag:FLAG}

P{UAS-Flag-mSpop.DeltaMATH}

Mmus\Spop^{ΔBTB.UAS.Tag:FLAG}

P{UAS-Flag-mSpop.DeltaBTB}

Mmus\Spop^{Δ3box.UAS.Tag:FLAG}

P{UAS-Flag-mSpop.Delta3box}

Mmus\Spop^{Y87N.UAS.Tag:FLAG}

P{UAS-Flag-mSpop.Y87N}

Mmus\Spop^{F102C.UAS.Tag:FLAG}

P{UAS-Flag-mSpop.F102C}

Mmus\Spop^{S119N.UAS.Tag:FLAG}

P{UAS-Flag-mSpop.S119N}

Mmus\Spop^{F125L.UAS.Tag:FLAG}

P{UAS-Flag-mSpop.F125L}

Mmus\Spop^{W131G.UAS.Tag:FLAG}

P{UAS-Flag-mSpop.W131G}

Mmus\Spop^UAS.Tag:FLAG

P{UAS-Flag-Spop}

Hsap\GLI2^UAS.cNa

PBac{UAS-hGLI2.N}

w¹¹¹⁸; PBac{UAS-hGLI2.N}VK00033

Hsap\GLI2^UAS.Tag:MYC

P{UAS-hGLI2.MYC}

Mmus\Gli2^UAS.Tag:MYC

P{UAS-mGli2.MYC}

Selected Drosophila transgenes

Allele

Transgene

Publicly Available Stocks

ci^{-3P.UAS.W.Tag:HA}

P{UAS-ci.HA.-3P}

RNAi constructs available

Allele

Transgene

Publicly Available Stocks

y¹ v¹; P{TRiP.HMJ23860}attP40/CyO

w¹¹¹⁸; P{GD1403}v51479

y¹ v¹; P{TRiP.JF01715}attP2

ci^JF01271

P{TRiP.JF01271}

y¹ v¹; P{TRiP.JF01271}attP2

ci^JF01272

P{TRiP.JF01272}

y¹ v¹; P{TRiP.JF01272}attP2

ci^JF01744

P{TRiP.JF01744}

y¹ v¹; P{TRiP.JF01744}attP2

y¹ sc^* v¹ sev²¹; P{TRiP.HMC06650}attP40

Selected Drosophila classical alleles

Allele

Allele class

Mutagen

Publicly Available Stocks

ci^DR50

loss of function allele

gamma ray

ci^D

loss of function allele

X ray

ci^D / l(4)102ABd⁴

ci⁹⁴

loss of function allele

Delta2-3 transposase

P{hsFLP}12, y¹ w^*; P{ci^+tWa}2L P{neoFRT}40A; ci⁹⁴

rdx¹¹

amorphic allele - genetic evidence

ethyl methanesulfonate

References (4)

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