Growth Autonomy 1

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Cyclins and cyclin dependent kinases (CDKs)
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Terms in this set (35)
Cyclins and cyclin dependent kinases (CDKs)
what coordinates the cell cycle phases?
- transcription of its gene
- regulated degradation at the protein level
what does the concentration of cyclin depend on?
the binding to cyclins
what are cdks activated by?
p21 and p27
what inhibits cdks by binding to them?
they are growth factors that are molecules that can induce mitosis and commit cells to pass through the G1 restriction point
what are mitogens?
Cyclin D
Growth factor signalling drives production and stability of what targeted protein?
Helps drive G1/S phase transition
what is the role of cyclin D
Ras
progression through G1 checkpoint is facilitated by the coordination of different what induced signal transduction pathways?
kinase part of receptors will autophosphorylates itself
what happens after EGFR dimerise?
GRB2
what intracellular signalling protein locks onto EGFR?
SOSwhat does GRB2 bind to?- Ras activate RAF, which is at the top of a MAPK cascade - RAF activates MEK, which activates MAPK - MAPK translocates into the nucleus where it phosphorylates molecules involved in driving the cell cyclethe activation of Ras by SOS causes wat cascade of events after?- it also simultaneously activates other signalling transduction cascades that are essential for cell cycle to occur - Ras can directly bind to PI3Kwhy is Ras so important in the EGF signalling pathway?- Raf/MAPK - PI3K/Aktwhat are the 2 main pathways Ras activates?- PI3K converts PIP2 into PIP3 - this activates AKT - AKT can translocate into the nucleus to phosphorylate transcription factors and can stimulate lipid and nucleotide synthesiswhat happens after Ras binds to PI3K?- Ras activates Raf (has 3 isoforms) - Raf phosphorylates and activates MEK (has 2 isoforms) - MEK phosphorylates and activates ERK (has 2 isoforms) - ERK can translocate into the nucleus and phosphorylate TF involved in driving cell cyclewhat is the detailed pathway of the Raf/MEK/ERK pathway (Ras/MAPK)?Ras facilitates the shape change in Raf which allows it to dimerise which is the first part of Raf activationHow does Ras activate Raf?- AP-1 TFwhat is one of the key target TFs of ERK?- its a dimer composed of Fos and Jun proteinwhat is AP-1 composed of?- by phosphorylating and activating other TFs that regulate Fos and Jun expression - influences amount of available AP-1 in nucleushow does ERK induce AP-1 activity?cyclin Dactivation of AP-1 TFs induce expression of what?- induces expression of cyclin D by activation of AP-1 TFs - increases levels of the cdk inhibitor p21 promotes the assembly of cyclin D-cdk 4 complexes via interactions with p21 - reduces level of cdk inhibitor p27what does Ras effect on cell-cycle components?- prevents proteosome-mediated degradation of cyclin D - represses transcription of cdk inhibitors p21 and p27 - phosphorylates and inhibits the cdk inhibitor p21what are the effects of the PI3K/Akt signalling pathway?Rbwhat does cyclin D activate to cause the progression of the cell from G1 to S phase?it is bound to histone deacetylase (HDAC) - makes chromatin more compact and represses transcriptionhow does Rb act as a tumour suppressor preventing cell cycle- cyclin D binds to cdk4 and activates it - cdk4 phosphorylates Rb - the phosphorylation allows the Rb protein to release HDAC - allows transcription of certain proteins, including Cyclin E - but Rb is still bound to E2F, therefore E2F target genes are not transcribed - Cyclin E binds to cdk2 ad activates it - cdk2 phosphorylates R on another site, allowing it to release its grip on E2F, therefore allowing transcription of E2F geneshow does repression get removed in order for cell division to occur?they are involved in S phase involved in DNA synthesiswhat are E2F genes involved in?the Raf and Ras mutational status of the patientprior to treatment with a receptor tryosine kinase (RTK) inhibitor what is essential to determine in order to predict drug response?- they bind to extracellular domain pf receptors and stop ligand from binding - also induces immune response through ADCP, ADCC and CDChow do monoclonal antibodies work as an anti-cancer therapy?cetuximaban example of a monoclonal antibody- competitively bind to the ATP binding site in the tryosine kinase - prevent phosphorylation and subsequent signal transductionhow do small molecule inhibitors work as an anti-cancer therapy?- type 1 - type 2 - type 3what are the different categories of small molecule inhibitors- mimic hydrogen bonds presented by ATP - not very specificwhat do the type 1 small inhibitors do?- occupy nearby hydrophobic pocket in an inactive kinase and allosterically affect kinase activitywhat do the type 2 small inhibitors do?- the most specific - covalently bind specific cyteines in target kinasewhat do the type 3 small inhibitors do?