Graeme Finlay 5 Flashcards
What are the cell cycle checkpoints?
They are points controlled by cyclin dependant kinases (which have their own activity regulated by cyclin concentrations). These points control if the cell will proceed through the cell cycle or not. They exist between G2 and M phase, G1 and S phase and in S progression
How is cdk activity regulated?
It binds to its cyclin and then has two inhibitory phosphorylation by wee1 kinase inhibitory. This then allows an activating phosphorylation by cyclin-activating kinase. The final step in cdk activation is the removal of the inhibitory phosphates by Cd25 phosphatase
What cyclins and cdks regulate the various checkpoints of the cell cycle?
The G1 to S phase point is passed by Cdk2 which is regulated by cyclin E, the continuation of S phase is also controlled by cdk2 but insteads requires Cyc A. The G2 to M phase transition is passed by cdk1 which is regulated by Cyclin B.
The cdks have a relatively constant presence in the cell while the cyclins are rapidly and transiently expressed with rapid degradation
What is the RB gene?
A gene where inactivating mutations cause paediatric retinoblastoma. The functional gene usually initiates cellular maturation switching cells from a proliferating to differentiating mode.
How does pRB help to regulate the cell-cycle?
pRB can be phosphorylated in many different locations and undergoes cycle dependant phosphorylation with a hypo-phosphorylated form in G0 or G1 and a hyper phosphorylated form for all other cell cycle phases, suggesting the hypophosporylated form mediated cell cycle entry
How did viral protein interactions with pRB help prove its role in cell cycle regulation?
Viral oncogenes such as the LT antigen of SV40 virus and E1A protein of adenovirus interact specifically with the hypophosphorylated form of pRB
How was the BCL-1 gene first located?
Mantle B cell lymphomas have a characteristic t(11:14) with an oncogene believed to lie at the breakpoint on chromosome 11 as it was translocated into the IgH locus.
What did the BCL-1 gene turn out to be?
A rearranged parathyroid oncogene was identified as the gene for a novel cyclin, cyclin D1 causing BCL-1 to be renamed and it was alos found to be over expressed in cancer cells
How does Cyclin D1 function?
They are induced in response to growth factors and activation of the Ras pathway leading to activation of Cdk4 and Cdk6 but do not oscillate during the cell cycle.
The key substrate of CycD-Cdk4 is pRb, which must be phosphorylated In order for the cell to traverse the restriction point
How does pRb regulate transcription?
The hypophosphorylated from of pRb interacts with proteins that regulate transcription, modification and remodelling of chromatin. pRb typically promotes the formation of heterochromatin silencing genes. This includes transcription factors and coactivators of all RNA polymerases.
As such loss of pRb reactivates all of these processes
Hypophosphorylation also activates transcriptional regulator proteins which induce differentiation
What is upstream binding factor?
This controls rRNA synthesis by RNA polymerase I
What is E2F?
Something which induces proteins necessary for S phase including RNA polymerase II and cyclin E which ensures that S phase entry is irreversible
What are TFIIB and TFIID?
Transcription factors which control expression of 5S rRNA, tRNA and snRNAs by RNA polymerase III
What is CDKN2alpha?
It is a gene located at chromosome 9p21 encoding the p16 inhibitor of cyclinD-Cdk4 and has its expression induced by Ras-Erk-Ets pathway.
How does TGFbeta interact with cell cycle regulation?
It blocks the hyperphosphorylation of pRb causing loss of cyclin D-Cdk4 activity blocking the cell cycle in late G1
It induces p15 which binds to cdk4 preventing its activation of cyclin D
It can also cause reduction of Cdk4 expression
