Human Disease Model Report: cancer, intestinal stem cell models

General Information

Name

cancer, intestinal stem cell models

FlyBase ID

FBhh0000767

Disease Ontology Term

intestinal cancer

Parent Disease

OMIM

Overview

The Drosophila posterior midgut is closely analogous to the mammalian small intestine; the midgut epithelium is maintained by frequent division of self-renewing intestinal stem cells (ISCs). This system has been extensively characterized in the context of general models of epithelial homeostasis. Developmental signals and signaling pathways, including signaling within the local microenvironment, have been characterized.

Development of differentiated absorptive and secretory gut cell types requires Notch signaling; loss of Notch (N) function in the posterior midgut results in stem cell tumor formation. This system has been exploited by using targeted RNAi-effected loss of N expression in the ISCs to investigate triggers for and downstream effectors of stem cell tumorigenesis. See Singh et al., 2019 (FBrf0243415), for a recent review and summary.

Up to 10% of aged wild-type males are found to have at least one stem-cell tumor in the gut. Since N is sex-linked, Drosophila males are susceptible to effects of spontaneous somatic loss of the N gene. Many of the spontaneous tumors were shown to have genetic lesions that affected the Notch region.

Drosophila adult stem cells have been found to be resistant to radiation- or chemical-induced apoptosis, thus providing a means to investigate mechanisms of resistance of stem cell tumors to various anticancer therapies.

This system has been used to characterize regulation of mitochondrial pyruvate metabolism in stem cell maintenance and differentiation and the role of Dmel\Mpc1 (ortholog of human MPC1) in that process.

The intestinal stem cell model has also been used to study colorectal cancer, by expressing implicated genes or gene variants in ISCs. See human disease model reports listed in "Related Diseases" section, below, for additional models based on this system.

[updated Oct. 2019 by FlyBase; FBrf0222196]

Disease Summary Information

Disease Summary: cancer, intestinal stem cell models

OMIM report

Human gene(s) implicated

Symptoms and phenotype

Genetics

Cellular phenotype and pathology

Molecular information

External links

Gene Cards: NOTCH1 gene
NCBI (Entrez) gene: NOTCH1 notch 1
Gene2Function (human gene): NOTCH1
MARRVEL (gene): NOTCH1

Disease synonyms

intestinal cancer

Related Diseases

Related human health report(s)

cachexia, yki-induced ISC tumor model

cancer, intestinal dysplasia, UVRAG-related

cancer, intestinal stem cell, APC-RAS-related

cancer, intestinal stem cell, APC-RAS-SNA-related

cancer, intestinal stem cell, RAS-related

cancer, intestinal stem cell, SRC-related

cancer, intestinal stem cell (postulated), SNX9,18,33-related

cancer, ISC, intercellular feedback loop, SOX-related

cancer, multiple, Notch signaling pathway

cancer, multiple, RAF1-related

colorectal cancer

Ortholog Information

Human gene(s) in FlyBase

Other mammalian ortholog(s) used

D. melanogaster Gene Information (1)

Dmel\N

Gene Snapshot

Contributions welcome

Molecular function (GO)

Cellular component (GO)

Gene Groups / Pathways

Comments on ortholog(s)

Moderate- to high-scoring ortholog of human NOTCH1, NOTCH2, NOTCH3, NOTCH4 (1 Drosophila to 4 human). Dmel\N shares 43-44% identity and 56-57% similarity with NOTCH1 and NOTCH2.

Orthologs and Alignments from DRSC

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

H. sapiens (Human)

Synthetic Gene(s) Used (0)

Summary of Physical Interactions (50 groups)

protein-protein

Interacting group

Assay

References

two hybrid, electron microscopy, molecular weight, enzyme linked immunosorbent assay

(Kelly et al., 2010, Pei and Baker, 2008, Fortini and Artavanis-Tsakonas, 1994)

N - Akap200

anti tag coimmunoprecipitation, anti tag western blot, western blot

(Bala Tannan et al., 2018)

N - arm

anti bait coimmunoprecipitation, western blot

(Hayward et al., 2005)

N - Caf1-55

anti tag coimmunoprecipitation, anti tag western blot

(Yu et al., 2013)

N - Caf1-105

anti tag coimmunoprecipitation, anti tag western blot

(Yu et al., 2013)

N - Caf1-180

anti tag coimmunoprecipitation, anti tag western blot

(Yu et al., 2013)

N - Cdk8

pull down, western blot

(Park et al., 2003)

N - CG10916

experimental knowledge based

(Guruharsha et al., 2011)

N - Chi

pull down, western blot, anti tag coimmunoprecipitation

(Sachan et al., 2015)

N - cno

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

(Pérez-Gómez et al., 2013, Carmena et al., 2006)

N - crb

proximity ligation assay, fluorescence microscopy

(Nemetschke and Knust, 2016)

N - D

affinity technology, tag visualisation by alkaline phosphatase activity

(Pérez et al., 2005)

N - Dab

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

(Kannan et al., 2018, Le Gall et al., 2008, Le Gall and Giniger, 2004, Giniger, 1998)

N - Dl

affinity technology, tag visualisation by alkaline phosphatase activity, pull down, inferred by author, fluorescence microscopy, bead aggregation assay, anti bait coimmunoprecipitation, western blot, enzyme linked immunosorbent assay, tag visualisation, atomic force microscopy, phenotype-based detection assay

(Pandey et al., 2019, Yamamoto et al., 2012, Acar et al., 2008, Pei and Baker, 2008, Xu et al., 2007, Parks et al., 2006, Ahimou et al., 2004, Bruckner et al., 2000, Rebay et al., 1991, Fehon et al., 1990)

N - dsh

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

(Capilla et al., 2012, Muñoz-Descalzo et al., 2010, Hayward et al., 2005, Ramain et al., 2001, Axelrod et al., 1996)

N - dx

two hybrid, anti tag coimmunoprecipitation, western blot

(Shimizu et al., 2014, Muñoz-Descalzo et al., 2010, Matsuno et al., 1995, Diederich et al., 1994)

N - Eogt

enzymatic study

(Sakaidani et al., 2011)

N - htk

anti bait coimmunoprecipitation, anti tag western blot, two hybrid, anti tag coimmunoprecipitation, western blot

(Singh et al., 2019)

N - Kap-α3

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

(Sachan et al., 2013)

N - kuz

protease assay, western blot, inferred by author

(Pan and Rubin, 1997)

N - lilli

anti tag coimmunoprecipitation, anti tag western blot

(Liu et al., 2017)

N - mam

anti tag coimmunoprecipitation, peptide massfingerprinting, protein three hybrid, three hybrid

(Gahr et al., 2019, Nagel et al., 2017, Yuan et al., 2016, Maier et al., 2011, Veraksa et al., 2005, Petcherski and Kimble, 2000)

N - MED17

pull down, western blot

(Park et al., 2003)

N - MED21

pull down, western blot

(Park et al., 2003)

N - MED31

pull down, western blot

(Park et al., 2003)

N - msn

coimmunoprecipitation, western blot

(Mishra et al., 2015)

N - ND-30

anti tag coimmunoprecipitation, western blot

(Lee et al., 2013)

N - Nedd4

anti tag coimmunoprecipitation, western blot, pull down

(Sakata et al., 2004)

N - numb

two hybrid, pull down, autoradiography

(Guo et al., 1996)

N - O-fut1

anti tag coimmunoprecipitation, western blot, anti tag western blot

(Sasamura et al., 2007, Okajima et al., 2005)

N - Pink1

anti tag coimmunoprecipitation, western blot

(Lee et al., 2013)

N - Pngl

experimental knowledge based

(Guruharsha et al., 2011)

N - polo

experimental knowledge based

(Guruharsha et al., 2011)

N - pyd

anti tag coimmunoprecipitation, anti tag western blot

(Shimizu et al., 2017)

N - Rbfox1

anti bait coimmunoprecipitation, western blot

(Shukla et al., 2017)

N - sca

anti tag coimmunoprecipitation, western blot

(Petruccelli et al., 2018)

N - Ser

inferred by author, confocal microscopy, bead aggregation assay, affinity technology, tag visualisation by alkaline phosphatase activity, pull down, tag visualisation, anti tag coimmunoprecipitation, western blot, fluorescence microscopy

(Pandey et al., 2019, Pérez-Gómez et al., 2013, Yamamoto et al., 2012, Kim et al., 2010, Xu et al., 2007, Pérez et al., 2005, Rebay et al., 1991)

N - shg

anti bait coimmunoprecipitation, western blot

(Sasaki et al., 2007)

N - spdo

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

(Upadhyay et al., 2013, O'Connor-Giles and Skeath, 2003)

N - Su(dx)

nuclear magnetic resonance, pull down, molecular weight estimation by staining, autoradiography, western blot, isothermal titration calorimetry, predetermined participant

(Yao et al., 2018, Jennings et al., 2007, Wilkin et al., 2004)

N - Su(H)

anti bait coimmunoprecipitation, anti tag western blot, western blot, pull down, autoradiography, anti tag coimmunoprecipitation, peptide massfingerprinting, two hybrid, protein three hybrid, isothermal titration calorimetry, predetermined participant, coimmunoprecipitation, cosedimentation, molecular sieving, molecular weight estimation by staining, electrophoretic mobility shift assay, electrophoretic mobility supershift assay, electron microscopy, three hybrid

N - Taf9

anti tag coimmunoprecipitation, anti tag western blot

(Xie et al., 2014)

N - Traf6

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

(Mishra et al., 2014)

N - trio

anti bait coimmunoprecipitation, western blot

(Kannan et al., 2018, Le Gall et al., 2008)

N - uif

anti tag coimmunoprecipitation, anti tag western blot

(Loubéry et al., 2014)

N - Vps26

anti tag coimmunoprecipitation, anti tag western blot

(Li et al., 2018)

N - Vps35

anti tag coimmunoprecipitation, anti tag western blot

(Li et al., 2018)

N - wry

inferred by author, confocal microscopy, bead aggregation assay

(Kim et al., 2010)

RNA-protein

Interacting group

Assay

References

N - Sxl

nucleic acid uv cross-linking assay, autoradiography, anti bait coimmunoprecipitation, quantitative reverse transcription pcr

(Penn and Schedl, 2007)

N - TBPH

pull down, quantitative reverse transcription pcr

(Swain et al., 2016)

Alleles Reported to Model Human Disease (Disease Ontology) (10 alleles)

Models Based on Experimental Evidence ( 4 )

Allele

Disease

Evidence

References

N^DN.UAS

model of intestinal cancer

CEA

(Singh et al., 2016)

N^ICN.UAS

model of carcinoma

CEA with Mef2^UAS.cUa

(Pallavi et al., 2012)

CEA with egr^UAS.cUa

(Pallavi et al., 2012)

model of brain cancer

CEA

(Wang et al., 2006)

N^UAS.icd

model of central nervous system cancer

CEA

(Zacharioudaki et al., 2016)

N^int.U.UAS

model of cervical cancer

CEA with Hsap\UBE3A^UAS.cRa, HPV18\E6^UAS.Tag:MYC

(Padash Barmchi et al., 2016)

model of adenocarcinoma

CEA

(Casas-Tintó et al., 2016)

CEA with wupA^f06492

(Casas-Tintó et al., 2016)

model of central nervous system cancer

CEA

(Zacharioudaki et al., 2016)

Modifiers Based on Experimental Evidence ( 9 )

Allele

Disease

Interaction

References

N^DN.UAS

ameliorates carcinoma

modeled by Vps25^N55

(Herz et al., 2006)

N^ICN.UAS

exacerbates carcinoma

modeled by scrib¹

(Brumby and Richardson, 2003)

exacerbates cancer

modeled by Hipk^UAS.Tag:HA

(Blaquiere et al., 2018)

N^UAS.icd

model of central nervous system cancer

is ameliorated by hth^C1

(Zacharioudaki et al., 2016)

is exacerbated by mira^HMS00347

(Zacharioudaki et al., 2016)

is ameliorated by svp¹

(Zacharioudaki et al., 2016)

is ameliorated by hth^B2

(Zacharioudaki et al., 2016)

N^dsRNA.P.UAS

ameliorates carcinoma

modeled by Vps25^A3

(Vaccari and Bilder, 2005)

N^l1N-ts1

ameliorates amyotrophic lateral sclerosis type 17

modeled by Hsap\CHMP2B^Intron5.UAS

(Wilson et al., 2020)

ameliorates brain cancer

modeled by aurA⁸⁸³⁹

(Wang et al., 2006)

N^nd-1

ameliorates Schimke immuno-osseous dysplasia

modeled by Marcal1^UAS.cBa

(Morimoto et al., 2016)

N^nd-3

ameliorates Schimke immuno-osseous dysplasia

modeled by Marcal1^UAS.cBa

(Morimoto et al., 2016)

N^GD14477

ameliorates brain cancer

modeled by Vps35^E42

(Li et al., 2018)

N^JF02959

ameliorates rhabdoid cancer

modeled by Snr1^HMS00363, BacA\p35^UAS.cHa

(Xie et al., 2017)

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

Selected mammalian transgenes

Allele

Transgene

Publicly Available Stocks

Selected Drosophila transgenes

Allele

Transgene

Publicly Available Stocks

RNAi constructs available

Allele

Transgene

Publicly Available Stocks

w^*; P{UAS-N.dsRNA.P}9G

w¹¹¹⁸; P{GD14477}v27228/TM3

y¹ v¹; P{TRiP.JF02959}attP2

N^JF01637

P{TRiP.JF01637}

y¹ v¹; P{TRiP.JF01637}attP2

N^JF01043

P{TRiP.JF01043}

y¹ v¹; P{TRiP.JF01043}attP2

N^JF01053

P{TRiP.JF01053}

y¹ v¹; P{TRiP.JF01053}attP2

N^JF01356

P{TRiP.JF01356}

y¹ v¹; P{TRiP.JF01356}attP2

N^JF01693

P{TRiP.JF01693}

y¹ v¹; P{TRiP.JF01693}attP2

y¹ v¹; P{TRiP.HMS00001}attP2

N^HMS00009

P{TRiP.HMS00009}

y¹ v¹; P{TRiP.HMS00009}attP2

y¹ sc^* v¹ sev²¹; P{TRiP.GL00092}attP2

N^GLV21004

P{TRiP.GLV21004}

y¹ sc^* v¹ sev²¹; P{TRiP.GLV21004}attP2

Selected Drosophila classical alleles

Allele

Allele class

Mutagen

Publicly Available Stocks

N^ETX52

amorphic allele - genetic evidence

P-element activity

N^55e11

loss of function allele

spontaneous

N^55e11 rb¹/C(1)DX, y¹ w¹ f¹; Dp(1;2)51b/+

N^fa-g

loss of function allele

spontaneous

w^a N^fa-g; Rho1^E3.10/CyO

N^264-40

amorphic allele - genetic evidence

X ray

w^a N^264-40 rb¹/C(1)DX, y¹ w¹ f¹; Dp(1;2)72c21/+

N^FE1

loss of function allele

X ray

N^l1N-ts1

ethyl methanesulfonate

y¹ N^l1N-ts1 g² f¹/C(1)DX, y¹ w¹ f¹

N^S-317

loss of function allele

ethyl methanesulfonate

N^l1N-2

amorphic allele - genetic evidence

gamma ray

N^FX9

loss of function allele

X ray

N^FE2

loss of function allele

X ray

N^FX8

loss of function allele

X ray

N¹

loss of function allele

y¹ w^* N¹/FM7c, P{GAL4-twi.G}108.4, P{UAS-2xEGFP}AX

N^FX4

loss of function allele

X ray

N^eU10

loss of function allele

ethyl methanesulfonate

N^eAS7b

loss of function allele

ethyl methanesulfonate

N^60g11

amorphic allele - genetic evidence

X ray

N^FX2

loss of function allele

X ray

N^XL86

loss of function allele

ethyl methanesulfonate

N²

loss of function allele

N^FX5

loss of function allele

X ray

N^FX7

loss of function allele

X ray

N^Yi66

loss of function allele

ethyl methanesulfonate

N^264-47

loss of function allele

X ray

N^264-39

loss of function allele

X ray

w^ch2 N^264-39/FM4, B⁺

N^X81K1

loss of function allele

N³

loss of function allele

N^3b22

loss of function allele

ethyl methanesulfonate

N^FX6

loss of function allele

X ray

N^XK11

amorphic allele - genetic evidence

N^nd-1

loss of function allele

spontaneous

N^nd-1 rb¹

N^M1

loss of function allele

ethyl methanesulfonate

N^FX3

loss of function allele

X ray

N^FX1

loss of function allele

X ray

N^X114

loss of function allele

ethyl methanesulfonate

N^66l2

amorphic allele - genetic evidence

N^nd-3

X ray

N^nd-3 rb¹/C(1)DX, y¹ f¹

References (35)

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