Graeme Finlay 8 Flashcards
(20 cards)
What G protein couples receptors have been mutated in tumours?
Thyroid-stimulating hormone receptor
Luteinising hormone/ chorionic gonadotrophin receptor
Follicle-stimulating hormone receptor
A large and poorly understood class of adhesion-related GCPRs
Lysophosphatidic acid and shigosine-1-phosphate receptors
How does lysophosphatidic acid and shigosine-1-phosphate receptor?
LPA and S1P are lipid components of serum supporting proliferation and migration by signalling through their receptors and Galpha 12/13 to suppress LATS and induce YAP/TAZ
How does ligand binding affect G receptors?
Ligand binding or mutations cause movement of helix IV creating a pocket for G protein engagement and guanine nucleotide exchange
What do mutations affecting Galphas and G alphaq proteins have in common with Ras protein mutations?
The mutations behave analogously to Ras mutation. Where GTPase activity is suprreseed causing them to remain in the active conformation for an extended period of time
What is one of the proposed ways in which the Galphas mutants may be playing a role in cancer?
Some Galphas transmit signals from proinflammatory GPCRs and mutants may therefore mimic chronic inflammation
What type of mutations occur in signalling pathways that respond to stress?
Activating mutations including KEAP1 mutations activating NRF2 in the anti-oxidant response, Altered regulation of the HIF1 transcription factor from the hypoxia response, The XBP1 transcription factor from the unfolded protein response
What are oncometabolites?
Metabolic substrates that when produced in altered concentrations affect cell cycle regulation
What is hereditary leiomyomatosis and renal cell carcinoma?
A cancer syndrome which involves two tumours, leiomyomas which are both cutaneous and uterine and early onset of multifocal renal cysts and aggressive papillary carcinomas
How is the key tumour suppressor gene in hereditary leiomyomatosis and renal cell carcinoma affected in cancer?
The gene encodes fumarate hydratase and undergoes two-hit loss of function mutations.
This results in reduced oxidative phosphorylation and increased glycolysis leading to suppression of AMPK and stimulation of fatty acid and protein synthesis as well as a uild up of fumarate
How does fumarate build up affect cells?
Fumarate acts to inhibit prolyl hydroxylase which is an alpha-ketoglutarate dependant enzyme which degrades HIF1alpha under normoxic conditions. The build-up of HIF1alpha results in induction of glycolysis enzymes and VEGF
Succination leading to enhanced anti-oxidant responses
What is succination?
When fumarate binds to proteins such as KEAP-1 which leads to reduced degradation of transcription factor NRF2
What is a gain of function mutation on a metabolic enzyme commonly found in astrocytomas?
Isocitrate dehydrogenase which acts as a neomorphic enzyme generating the oncometabolite 2-hydroxyglutarate
This enzyme is commonly mutated through a CpG island methylator phenotype
TET-2 mutations may occur instead of Isocitrate dehydrogenase as these mutations are mutually exclusive
What is the link between TET-2 and Isocitrate dehydrogenase mutations in astrocytomas?
They are mutually exclusive mutations, both mutations prevent converstion of 5mc into 5hmc causing associated Tumour suppressing genes to be silenced
How can lineage specific transcription factors act as oncogenes?
These genes normally drive differentiation but they may be highly expressed in cancer to promote the survival of specific cancer cells
What are examples of lineage specific transcription factors acting as oncogenes?
The MITF-M isoform in melanoma
SOX2 in oesophageal cancer
CDX2 in colorectal cancer
How can histone modification aid in cancer development?
Chromatin function is controlled by posttranslational modifications of histone tails. Reccureent changes may occur in enzymes that add or remove acetyl groups and methyl groups
How can nucleosome remodelling act in cancer?
Compaction of DNA is necessary to maintain genomic stability and silence lineage specific genes that maintain stemness. Loss of function mutations often affect multiple components of the SWI/SNF regulatory complexes
What are examples of DNA methylation playing a role in cancer?
Loss of DNMT3b and of TET2
How can RNA splicing play a role in cancer?
Components of the RNA spliceosome are frequently mutated which may affect the selection of mRNAs species which encode lineage-specific differentiation factors
How can protein synthesis and degradation play a role in cancer?
Many components of the E3 ubiquitin ligases are mutated. This may affect substrate specificity and allow accumulation of oncogenic proteins
