2 - Rb Flashcards
What is retinoblastoma?
A rare childhood cancer of the eye where a mass of cells displace the retina and can also grow and displace the optic nerve
What percent of cases of retinoblastoma are familial
40%
Describe the two hit hypothesis in relation to retinoblastoma
Due to the high hereditary indicence of retinoblastoma it was thought something must increase the risk of developing it. The herefitary cases are born with one copy of the gene already, making the risk increase as it is easier to gain one mutation then two
Cancer is multihit, what does this mean?
More than one gene is affected to present the ten hallmarks of cancer
What are the seven ways by which a second hit can occur
Nondisjunction when the cell divides (loss of a chromosome), nondisjunction and duplication, recombination, deletion, point mutation, methylation, gene conversion
Methylation of the promoter gives??
Epigenetic silencing of gene expression, by induction of chromatin
Where is a deletion observed in retinoblastoma?
Chromosome 13q14.1
Describe Rb
Rb is a 200kb gene, encoding a nuclear protein
Rb is modulated by?
Phosphorylation state
Rb function?
Regulation of the cell cycle
What are the sister proteins of Rb?
p107 & p130
How does Rb regulate the cell cycle?
The phosphorylation state of Rb alters throughout the cell cycle
In G1 it is hypo-phosphorylated. Once past the restriction point there is progressive phosphorylation until dephosphorylation at the end of mitosis. Rb binds the transcription factor E2F 1/2/3 DP 1/2 which it binds and represses in hypo-phosphorylation by recruiting HDAC. This means the genes it transcribes relating to the cell cycle cannot be transcribed.
With phosphorylation, Rb cannot bind the transcription factor. It can thus, recruit HA and induce transcription.
What is responsible for the hypo phosphorylation in G1?
Cyclin 4/6
What is responsible for the progressive increase in phosphorylation following the restriction point?
Cyclin 2, entering a positive feedback loop of phosphorylation
What would be the impact of Rb loss?
It inhibits gene transcription, arresting the cell in G1. If this didn’t occur the cell could divide continuously.
