Search for notes by fellow students, in your own course and all over the country.
Browse our notes for titles which look like what you need, you can preview any of the notes via a sample of the contents. After you're happy these are the notes you're after simply pop them into your shopping cart.
Document Preview
Extracts from the notes are below, to see the PDF you'll receive please use the links above
Wnt, TGF-Beta and Hippo Signalling
Wnt Signalling:
1
...
2
...
3
...
4
...
5
...
6
...
7
...
8
...
Certain Wnts, acting together with a subset of the Frz receptors, signal through an
entirely different biochemical pathway, termed “non-canonical Wnt signalling”
...
This pathway is said to play a key role in the control by Wnts of various cancer cell
phenotypes, including motility, invasiveness, and the maintenance of self-renewal
potential
...
The non-canonical Wnt proteins regulate G-proteins (binary on-off switches that
cycle between a GTP-bound active state and a GDP-bound inactive state)
...
Colon cancer is the 4th most common cancer after lung, prostate, and breast cancers,
and is the second leading cause of cancer mortality
...
Deregulation of Wnt signalling is the first step in colon cancer
...
The functions of the colon include:
• Reabsorption of water and inorganic salts
• Secretion of mucus that acts as a lubricant during the transport of the
intestinal contents
...
The villi of the small intestine are tiny, finger-like projections that protrude from the
epithelial lining of the intestinal wall
...
Each villi has microvilli, and they function is to increase the amount of surface area
available for the absorption of nutrients
...
The villi are made up of four different types of cells:
• Enterocytes – secrete hydrolases and absorb nutrients
• Enteroendocrine cells – hormone producting
• Goblet cells – mucus producing
• Paneth cells – secrete antimicrobial agents
7
...
8
...
9
...
• Each crypt produces about 200 cells per day
...
10
...
Canonical Wnt Signalling:
1
...
2
...
All of these mutations are associated with an increase in bcatenin levels
...
GSK3 phosphorylation sites are mutated or absent – thus no phosphorylatedinduced tagging of b-catenin for degradation à constitutive signalling
...
Rnf43 – part of the negative feedback loop on stem cells that inhibits
proliferation
...
e
...
1
...
2
...
3
...
This is
found at elevated levels in 90% of colon cancers
...
Ephrin receptors, EphB2 and EphB3, and their ligand, ephrin B1 – involved in cell
migration from the crypts to the top of the villus
...
5
...
6
...
APC (adenomatous polyposis coli):
1
...
2
...
3
...
4
...
5
...
6
...
7
...
8
...
9
...
10
...
11
...
12
...
à The interactions of the microtubule-binding domain are important for proper regulation
of cell motility and mitosis
...
Together with the two scaffolding proteins: axin and conductin, APC forms a
multiprotein complex that brings together GSK-3b and b-catenin
...
This association enables the degradation of b-catenin, thus in the absence of APC, bcatenin levels can accumulate to high levels within cells, even in the absence of Wnt
signalling
...
With a second mutational “hit”, the adenomatous polyps become adenocarcimona’s
and eventually metastatic cancer
...
The Canonical TGF-b Signalling Pathway:
Recap:
1
...
2
...
3
...
4
...
5
...
6
...
TGF-b controls the cell cycle machinery in part through its ability to modulate the
levels of CDK inhibitors
...
It acts strongly to induce increased expression of p15 and weakly, of p21
...
P15 can block the actions of cyclin D-CDK4/6 complexes, while p21 can block the
actions of the remaining cyclin-CDK complexes that are active throughout the
remainder of the cell cycle
...
Additionally, TGF-b can cause cell death independently of Smad proteins but also
with Smad proteins
...
TGF-b and BMPs in Differentiation:
1
...
2
...
3
...
4
...
5
...
It is a result of mutations in Smad4 (co-Smad) and BMPR1A (BMP
receptor 1A)
...
Intrinsically:
• TGFb promotes the epithelial-to-mesenchymal transformation and motility
...
e
...
2
...
Because of its role as a tumour as both tumour suppressor and promoter, TGF-b
expression is correlated with the tumour grade, in that, the more it’s expressed in
the cells, the higher the tumour grade
...
Hereditary nonpolyposis colorectal cancer (HNPCC) patients who have lost the TGF-b
receptor 2 have a better prognosis than sporadic cancer patients with an intact TGFb
signalling
...
This is because they have lost the entirety of the response to the molecule and thus
have reduced the chances of a metastatic phenotype developing
...
Partial signalling has some responses still intact, and thus cells can become
cancerous and invasive, i
...
they maintain their intrinsic properties
...
Epithelial cancer cells (blue cells) at the edge of a primary carcinoma undergo an
EMT as they invade the stroma and become mesenchymal (red cells)
...
This change is triggered by signals that these carcinoma cells receive from nearby
tumour-associated reactive stroma, which is composed of a variety of inflammatory
cells that accumulate during the long course of primary tumour formation
...
The newly acquired mesenchymal state enables the carcinoma cells to invade locally,
intravasate, and subsequently extravasate into the parenchyma of a distant,
ostensibly normal tissue
...
5
...
7
...
In one experiment where ras-transformed EpRas mouse mammary epithelial cells
were exposed to TGF-b, resulted in the progressive loss of epithelial morphology and
a reduction in epithelial markets, such as E-cadherin, and cytokeratins
...
Interestingly, once these cells underwent EMT, they begun to produce their own
TGFb, thus allowing them to maintain their mesenchymal phenotype for extended
periods of time, long after the inciting TGFb was withdrawn from the culture
...
Additionally, TGFb and BMP signalling, both Smad-independent pathways, can also
increase EMT by disinhibiting the cofflin inhibition of the dynamic transition of Gactin to F-actin, and vice versa
...
TGFb can promote metastasis at secondary sites: exposure of breast cancer cells to
TGFb causes them to release other factors that accelerate the breakdown of
mineralized bone
...
This is a key step in the formation of osteolytic metastases and this liberates
additional mitogens that drive cancer proliferation
...
TGFb also promotes angiogenesis and is a potent cheomoattractant for monocytes,
which release angiogenic cytokines
...
Additionally, further perpetuating the cancer phenotype, TGFb is capable of
suppressing the immune system by:
• Downregulating the proliferation of immune cells, i
...
CD8 T cells
• Upregulating the cell death of immune cells, i
...
B cells
...
Hippo signalling is an evolutionary conserved pathway that controls organ size by
regulating cell proliferation, apoptosis, and stem cell renewal
...
In addition, dysregulation of the Hippo pathway contributes to cancer development
...
Core to the Hippo pathway is a kinase cascade, wherein Mst1/2 kinases and SAV1
form a complex to phosphorylate and activate LATS1/2
...
In turn, LATS1/2 kinases phosphorylate and inhibit the transcription co-activators
YAP and TAZ, two major downstream effectors of the Hippo pathway
...
When dephosphorylated, YAP/TAZ translocate into the nucleus and interact with
TEAD1-4 and other TFs to induce expression of genes that promote cell proliferation
and inhibit apoptosis
...
There are several cell or tissue properties that regulate Yap/Taz activity, these
include:
• Mechanotransduction
• Cell-cell adhesion
• Contact inhibition
7
...
8
...
This is
because Lats2 overexpression increases Rb-mediated silencing of E2F target genes
that are involved in cell proliferation
...
Overall, somatic germ line mutations in the core hippo pathway are rare, but are
found as passenger mutations (i
...
mutations that confer no selective advantage on
a cell carrying it) in many cancer including lung, colorectal, ovarian, liver and
prostate cancers