Biology 3 - Cancers are Genetic Diseases (Keith Spriggs) Flashcards
How are growth signals transduced?
By signalling pathways; involving the products of oncogenes and tumour suppressor genes
How are the effects of tumour suppressor genes and oncogenes ultimately observed?
In gene expression changes
What is a gene?
It is not universally agreed; for the purposes of this module it is a functional unit of inherited DNA. In mammals, one gene encodes for one protein. We have two copies of every gene, one maternal and one paternal.
What are oncogenes?
Aberrant (mutated) versions of proto-oncogenes.
Proto-oncogenes act in healthy cells to promote proliferation and survival. If proto-oncogenes are inappropriately activated or over-expressed (e.g. by mutation) then they become oncogenes.
What are tumour suppressor genes?
The products of tumour suppressor genes protect against cancer initiation and progression.
Pro-apoptotic
If tumour suppressor cells are inactivated or repressed (e.g. by mutation), cancer is more likely.
How is DNA translated into protein?
Gene encoding for one protein (a.k.a a sequence of nucleotides)
RNA polymerase transcribes to pre-mRNA; this has to undergo splicing to remove introns. Exons are ligased and then translated to protein.
How are genes regulated?
– Chromatin remodeling – Transcription – mRNA processing (splicing, stability) – microRNAs – Translation (protein synthesis) – Post translational modifications
What is ‘Epigenetics’? Give some examples.
Changes that affect gene expression without changing DNA base sequence. Histone modifications (acetylation or methylation) DNA modifications (cytosine methylation --> promotor repression)
Can be inherited by daughter cells
Alter the accessibility of DNA for transcription
What is chromatic?
DNA packaged and wrapped around histones
What determines how tightly packed chromatic are?
Modification of histone tails e.g. by acetylation and methylation determines how tightly packaged the DNA is
What is associated with ‘open’ chromatin domains?
Acetylation
What is associated with ‘closed’ chromatic domains?
Methylation
What need to remain free of histone in the chromatic complex?
Transcribed DNA that is upstream to allow RNA polymerase II complex to assemble.
What are HDAC inhibitors?
Histone Deacetylases (HDACs) remove acetyl groups from histones and induce p21. HDACs are therefore important, attractive drug targets (Vorinostat, Romidepsin, Panobinostat).
What are the effects of HDAC inhibitors in cancer?
HDAC inhibitors are anti-angiogenesis and promote apoptosis. they also induce p21 that leads to cell-cylce arrest/differentiation.
How is transcription controlled?
Transcription factors positively and negatively regulate how much mRNA is made for each gene.
Transcription factors and mediators cooperate to direct RNA pol II to start transcribing the gene.
What factors can transcription be affected by?
The amount of transcription of a gene often determines the amount of protein expressed.
Transcription can be affected by changes in protein levels (e.g. transcription factors)
Changes in DNA structure (e.g. histones, DNA methylation)
Changes in DNA sequence (e.g. mutation of transcription factor binding sites).
What is the role of p53?
It is a tetramer, transcription factor that binds to target promoters to regulate transcription
Detects when things are wrong and prevents proliferation (so this role gives it tumour suppressor properties).
How does p53 perform it’s regulatory role?
p53 tetramers bind (along with other transcription factors i.e. p21, BAX and p53R2
Down regulates proto-oncogenes such as VEGF and MYC
What happens if p53 is mutated?
Can be oncogenic
How is RNA processing control maintained?
Splicing
How can the splicing of Rb happen?
Retinoblastoma is a tumour supressor that inhibits transcription factors necessary for cell cycle progression.
If a single base mutation happens, the reading frame of RNA shifts and exon 22 can be spliced meaning that Rb is removed.
Exon 22 is missed giving rise to non-functional protein
What is UTR?
Untranslated region
What are microRNAs?
Short RNA molecules that don’t code for anything but that can bing to complementary 3’ UTRs of target mRNAs.
They can inhibit translation (protein synthesis)
They can cause mRNA degradation.
What are microRNAs that inhibit tumour suppressors?
Oncomirs
What are microRNAs that inhibit oncogenes?
Tumour suppressor miRs
What happens in mutations occur in mIRs or the binding sites?
Regulation cannot be maintained by the mIRs
What kind of mutation gives rise to Breast Cancer caused by BRCA1?
Mutation in BRCA1 3’ UTR changes the binding site for mIR-320 and so the microRNA can no longer maintain regulation.
How is translation regulated?
Complex control of gene expression
How do oncogenic mutations affect translation?
Increase the activity and abundance of ribosomes and translation factors
Via the MTORC pathway downstream of EGFR
What does a C –> T mutation in the 5’ UTR of MYC gene cause?
Increased ribosomal recruitment and leads to the increased synthesis of the oncoprotein MYC
What changes to post-translation modifications can cause cancer?
p53 function will be affected by PTMs
Ubiquitination (addition of ubiquitin by MDM2) targets p53 for degredation
