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Developmental Genetics and Embryonal Cancers > Signalling Pathways IN Development and Cancer > Flashcards

Signalling Pathways IN Development and Cancer Flashcards

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Biology 101 flashcards
1
Q

What are the 2 pathways invovle din cell-cell signalling

A

Notch

Hippo

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2
Q

What pathways are inovlved in larger distance

A

Wnt

Hedgehog

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3
Q

What are the notch receptors and ligands

A

4 Notch recepetors
5 ligands: DLL 1,3 and 4
Jagged 1/2

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4
Q

How are the Notch receptors synthesised

A

Synthesised as single precuros protein that is cleaved on the way to cell surgace by furin-like proteases
Expressed as a heterodimer; has 2 extracellular subunits and TM and cytoplasmic region
THe extracellular subunits have EGF-like repeats followed by 3 cystein LIN12/Notch repeats that prevent ligand-independent binding

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5
Q

How do ligands actovate Notch

A

2 successive proteolytic cleavages
First on the extraceullalar subunit near the TM domain by a metalloproteinase of the ADAM family
Extracellular subunit and ligand are endocytosed
Then mono-ubiquitination process follows which triggeres endocytosis of the TM Domain –> This liberates NCID which then rravels to the nucleus

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6
Q

How does nucelus cause transcription

A

NCID heterodimerises with CSL transcription factor
In the absence of Notch CSL fucntions as a transcriptional repression
NCID and CSL recuir transcription co-activators

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7
Q

WHat genes does notch cause transcitpion of

A

c-myc and CDKN

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8
Q

What does Nothc function in

A

Stem cell maintenance
Lateral signaling
Induction Signalling
Differenetiation and cell cucle arrest

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9
Q

What cancers in Notch implciated in

A

T-ALL

Breast cancer

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10
Q

What does Notch act as TSG

A

Notch deficient means that mice develop BCC

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11
Q

How does Nothc cause breast cancer

A

insertion of MMTV increase Notch 4 expression which is truncated
Notch 1 activity also increased in 50% of tumours

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12
Q

What is at the core of the hippo pathway

A

The core kinase cassette

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13
Q

What makes up the core kinase cassette of the hippo pathways

A

MST1/2 - kinase
LATS1/2 - TSG
SAV1A
MOB1A

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14
Q

What does the core kinase cassette repreess in the hippo ptahway

A

YAP/TAZ

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15
Q

What properties regulate the hippo pathway

A

Apico-basla polirty –> loss of ABCP proteins
Cell-Cell Adhesion - E cadherin can sequester it
Mechanotransduction
Contact Inhibition

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16
Q

What is the role of Hippo In Pathway

A

NF2 mutation in neurofibromatosis type II

YAP1 locus frequently amplified in cancer e.g. HCC and increasesd YAP nuclear localisation seen in cancer e.g. colon

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17
Q

What type of genes are Wnt and Hh in Drosophilia

A

Segment polarity genes

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18
Q

What does LOF mutaitons in Wnt cause

A

Tetra-amelia

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19
Q

What is the role of Wnt in development.homeostarsis

A

Invovled in patterning throughout the embrup
Essential for dorsal/ventral axis formation in the early embyro
Wnt Promotes proliferation and fiferentiation

20
Q

What is Hh role in development

A 
It is a classic morphogen
Causes different cell fates at different concentration
Controls midline formation
Regulates L/R aassymetry in the head
Regulates EMT interactions
Controls digit number and polairtyh
21
Q

Describe the Hh Pathway

A

Hh signalling binds to the Ptch1 receptor –> repression of Smo released –> allows expression and or post transclation processin oft he Gli transcription facotrs

22
Q

Hh rle in cancer

A

Loss of Patched in BCC
Activation mutaitons of Smo found in BCC
Also pathway activation found in glioma, medulloblastoma, fibrosarcoma

23
Q

What are the Notch target genes

A

Myc, CDKN, Hes

24
Q

What abherrant Notch signalling also occurs in breast cancer

A

c-kit and PDGFR expressionis increased

25
Q

What happens if you get MMTV insertion at notch 1

A

Less common

Get non-invasive papillary tumours that regress on gloand involution

26
Q

What is a negative notch regulator

A

Notch –> aggressive mammarry carcinomas often lose numb

27
Q

What other cancers is notch often mutated

A

Notch and pancreatic cancers

28
Q

What ocurs in pacnreatic cancerts

A

Upregulation of notch, ligands and targets increased in pre-neoplastic incasive lesions may be an early event in pancreatic cancer

29
Q

Which other pathway is there also an increase in Notch mediated signalling

A

Increase in TGF-alpha induced EGF signalling

30
Q

What organ does Notch act as a TSG in

A

The skin

get an upregulation of skin differentiatoin markers i.e. Keratin 1/10

31
Q

What does notch repress in the skin

A

Notch increases p21 and p21 can repress Wint4

32
Q

How can we target notch

A

Anti - DLL4 - Dll4 is a notc signalling component involved in angiogenesis
Small molecule inhibitors of gamma secretase –> prevents NCID release –> targets all notch receptors shown

33
Q

What has small molecule inhibitors of gamma secretase been inhibited in

A

Kaposis sarcoma as this overeperessed notch 1, 2 and 4 BUT bad SE Of treatment e.g. GI cytotxicity

34
Q

What can YAP Promote

A

YAP can promote EMt

35
Q

What is Hippo deregulated in

A

Lung and colon cancer

36
Q

What are their germline mutations of hippo in

A

Type 2 NF

37
Q

What other patways can deregulate Hippo

A

Wnt and TGF-B

B catenin can cause nuclear accumulation of Yap

38
Q

How can we target Hippo

A

Target Kinases

Target Yap - Verteporfin

39
Q

What is Verteporfin used for

A

Targeting YAP

Already used as a photosensitiser in photocoagulation therapy for the teratment of macular degerneation.

40
Q

What defect do you get with Wnt 1 deletion

A

Midbrain defect

41
Q

Discuss the structure of the Wnt Receptors

A

FXD and LRP5/6

has 7 TM and extracellular N terminus rich cysteine rich domain which is the primary Wnt binding site

42
Q

What other condition NOT CANCER is wnt deregulated

A

Hereditary osteoporosis

43
Q

What negatively regulates Wnt in bone

A

SOST –> we can give SOST inhibitors to treat hereditary osteoporosis

44
Q

What else can we inhibit to treat Wnt

A

Porcupine inhibitors –> as porcupine acetylate Wnt

45
Q

What is Hh mutated in

A

BCC and Gorlins syndrome

Also increased Hh Ligand in small cell lunc cnacner and pancreativ cancer

46
Q

Where is Hh secreted from

A

IN embyronic development the celles that secrete Hh are distinct from those that have receports. Thought this may also be the case in tumours in which the stromal cells screte Hh

47
Q

Ihibitors of Hh signalling

A

1) cyclopoamine –> inhibits Smo and succes seen in BCC
2) GANT-68 –> works downsteam of Smo and inhibits DNA binding but the precise mechanism is unknown
3) mAB to rpevent ligand binding

Developmental Genetics and Embryonal Cancers (18 decks)

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