Lecture 7 Retinoblastoma Flashcards
What decision must a cell make at the end of G1
Whether to commit to the rest of the cell cycle or whether to exit at this point and die
What is meant by the restriction point
The restriction point is a checkpoint at the end of G1t that blocks cell cycle progression unless nutrients and mitogens (growth factors) are continuously present
Cells require growth factors in order to proliferate in culture T or F
T
What is significant about the requirement of growth factors by cells in the cell cycle
Growth factors are actually only required at the restriction point in order to progress from G1 to S phase
Briefly describe the role of Rb in the cell cycle
The restriction point at the end of G1 that controls entry into S phase is controlled by the Rb protein
Which cancers have Rb been implicated in
Defective versions of Rb are involved in the pathogenesis of retinoblastomas sarcomas and several other cancers
Outline what happens at the restriction point in the absence of mitogens
In late G1 phase the genes involved in expressing proteins required for S phase are kept off for several reasons. Firstly the E2F transcription factor is unable to function because it’s bound to Rb which represses its function. Secondly Rb recruits’ histone deacetylases (HDAC) which deacetylate histones causing chromatin compaction which also aids to repress transcription
Which cyclin is upregulated by mitogens and mitogen signalling
Cyclin D
Unlike other cdks cyclinD-cdk4/6 is simply a mediator of mitogenic signaling T or F
T
How does cyclin D and cdk4/6 regulate Rb
Cyclin D and cdk4/6 play a critical role in controlling Rb function. Cyclin D binds to cdk4/6 pulling the activation loop away from the active site exposing the bound ATP. The cyclin D-Cdk4/6 complex can now phosphorylate target proteins such as Rb. Phosphorylation of Rb by cdk4/6 switches Rb to its hypo-phosphorylated form.
Describe the different phosphorylation forms of Rb
Newly synthesized Rb protein is present in an un-phosphorylated form phosphorylation by cyclin D-cdk4/6 switches Rb to its hypo-phosphorylated form. Then further phosphorylation by cdk2 switches Rb to its hyper-phosphorylated form
Describe how the regulation of cdk4/6 controls entry into S phase of the cell cycle
Phosphorylation of Rb by the cyclin D-cdk4/6 complex weakens its repression of E2F. This allows E2F to begin transcribing early S phase genes. One of these de-repressed genes that is now transcribed as a result of weakened repression by Rb is cyclin E. Once cyclin E is transcribed and translated it then binds cdk2 and activates it. Cdk2 further phosphorylates Rb to its hyperphosphorylated state. This means that Rb can no longer functional as a transcriptional repressor. This causes HDACs dissociate from the DNA and the chromatin subsequently adopts more open state. This allows E2F to transcribe all S phase genes
What specifically goes wrong in terms of the functions of Rb that causes the development of cancers
Cancers acquire mutations in Rb together with many components controlling progression through the restriction point. This acts to remove the dependence on mitogenic signalling for proliferation hence you get an over-proliferation of cells
