Common signalling pathways of development of cancer Flashcards
1
Q
What causes cancer?
A
- activation of oncogenes - overexpression/induction or gain of function
- loss of tumour suppressor genes - loss of wild type copy of the gene (loss of heterozygosity), loss of function mutations (p53)
2
Q
What processes occur during tumourigenesis?
A
- proliferation
- migration invasion
- apoptosis
- angiogenesis
3
Q
How are the developmental pathways involved in cancer?
A
- Cell survival = STAT, PI3K, RAS, MAPK, TGF-b
- Cell fate = NOTCH, HH, APC, chromatin modification
- Genome maintenance = DNA damage control
4
Q
Describe the TGF-b signal pathway
A
- Receptors - type I and II single-pass transmembrane receptor kinases
- Ligands - transforming growth factor beta superfamily including activins, nodal, bone morphogenic proteins (BMP), myostatin
- Mechanism - TGF-b ligands bind to a type II receptor which recruits and phosphorylates Smad 2/3, which can now bind the Smad4. This Smad 2/3/4 complex enters the nucleus where they induce gene expression by binding to a DNA sequence (CAGAC) in the promoters of target genes (p15- cell cycle inhibitor = G1 arrest)
5
Q
What is the function of TGF-b
A
- many cellular processes = cell growth, differentiation, apoptosis, homeostasis, inflammation, immunity
- normally inhibits the cell cycle (tumour suppressor)
- as the tumour progresses to malignancy, cells develop resistance to TGF-b mediated inhibition and TGF-b becomes a tumour promoting activity
- mutations in TGF-b receptors and Smads are found in many cancers including pancreatic and colorectal cancer
6
Q
Describe the Hedgehog signal pathway
A
- Receptor - Patched (Ptch1/2), a 12 pass transmembrane protein
- Ligands - Hedgehog protein (Hh) that is secreted and diffused to their targets, mammals have 3 types of Hh genes : Sonic, Indian and Desert
7
Q
What is the mechanism in Hh signalling?
A
- in the absence of the ligans, Ptch1 binds a 7 transmembrane protein called smoothened (Smo). The zinc finger transctiption factor Gli is proteolytially processed to generate C-terminally truncated Gli
- When Hh ligand binds to Ptch1, the Smo separates from Ptch1 enabling Smo to activate Gli. Activated Gli enters the nucleus and induces transcription of target genes
8
Q
What is the function of Hh signalling?
A
- vital for diverse developmental processes - regulation of cell fate and number in brain, spinal cord, patterning of limbs and internal organs; stem cell maintenance
- mis regulation of the Hh pathway causes birth defects (gorlin syndrome) and many cancers - basal-cell carcinoma, GI cancers
- cancer causing mutations cause extra-high levels of Hh or suppressed Ptch1 activity, both leading to elevated Gli activity
9
Q
Describe Wnt signalling?
A
- Receptors - frizzled, a 7-transmembrane protein, has the extracellular ligand-binding site and the intracellular effector site extending into the cytosol
- Ligand - secreted Wnt protein
10
Q
Describe the mechanism of Wnt
A
- in the absence of ligand, b-catenin is quickly destroyed by a multiprotein degradation complex
- the degradation complex phosphorylates B-catenin so it can be ubiquitinated, ready for destruction in proteosomes
- binding of Wnt ligand (with aid of LRP) activates Frizzled, which then activates dishevelled. Activated dishevelled inhibits the degradation complex and beta-catenin destruction b y the proteosomes, allowing accumulation of beta-catenin
- Beta-catenin enters the nucleus where it binds and activates TCF/LEF transcription factors including the expression of target genes (c-Myc)
11
Q
What is the function of Wnt signalling?
A
- controls gene expression in many roles in embryonic development (eg. a gradient from low at the future head to high at the future tail established the anterior-posterior axis)
- activating mutations in the human b-catenin gene were found in colon cancer and melanomas. Mutations in AXIN1 gene were reported in hepatocellular carcinomas
- mutations in the degradation complex lead to inappropriate stabilisation of b-catenin, resulting in persistant expression of oncogenes
12
Q
Describe Notch signalling
A
- first discovered in drosophila
- notch requires direct cell-to-cell contact
- Receptors - Notch, single-pass transmembrane glycoproteins four genes in vertebrates
- Ligands - single-pass transmembrane proteins Delta1/3/4 and Jagged 1/2 in mammals
13
Q
What is the mechanism in Notch signalling?
A
- when a cell bearing the ligand comes in contact with a cell displaying the notch receptor, the external portion of notch is cleaved away from the cell surface (engulfed by the ligand-bearing cell by enodocytosis)
- the internal portion of the notch receptor (NICD) is cut away from the plasma membrane and move to the nucleus
- NICD binds to the CSL/RBPJ transcription factor, converting in into a transcriptional activator by displacing a CoRepressor and recruiting coactivators (MAML) leading to activation of downstream target genes (Hes)
14
Q
What are the functions of the Notch pathway?
A
- regulates development of many virtual organs (brain, immune, endocrine, GI tract, heart)
- once cell tells an adjacent cell which path of differentiation to take
- mis-regulation of notch signalling has been implicated in T and B cell malignancies, breast cancer, skin cancer
15
Q
Describe FGF signalling
A
- Receptors - Fibroblast growth factor receptor (FGFR)
member of receptor tyrosine kinases, four genes in mammals (FGFR1-4) - 3 isoforms a,b,c - generated by alternative splicing of the extracellular domain
- Ligands - secreted FGFs, 23 FGFs with multiple isoforms, in mammals
