Describe three pathways of cell proliferation targeted for de-regulation in cancer Homework Help

Assignment 4: Describe three pathways of cell proliferation targeted for de-regulation in cancer

Pathway 1: Cyclin D-cdk-Rb-E2F

Extracellular signals stimulate a signalling pathway mediating cell proliferation

Almost any component of the signalling pathway can be de-regulated by activation of oncogenes.

Cyclin D expression is induced by this signalling. It binds partner cyclin dependent kinases (CDKs). Assembly is facilitated by the cyclin dependent kinase inhibitor (CDKI) p27 (does not inhibit cyclin D/CDK4 or 6), sequestering this molecule preventing its inhibition of downstream CDK’s.

Cyclin D/CDK4 or 6 phosphorylate retinoblastoma protein (RB)

Hyperphosphorylated RB dissociates from E2F enabling these transcription factors to activate expression of cyclin A and E and DNA metabolising genes.

p16 is a CDKI that inhibits cyclin D/CDK4 or 6.

Amplification of cyclin D activates an oncogene in this pathway

RB, p27 and p16 are all tumour suppressor genes that are targeted for inactivation in this pathway.

Pathway 2: ATM/ARF, CHK1/CHK2, MDM2, p53, p21

DNA damage pathway in G1 of cell cycle.

ATM/ATR recognise damaged DNA activating their serine/threonine kinase catalytic activity.

Target proteins phosphorylated include CHK1 and CHK2 kinases

CHK1/CHK2 kinase catalytic activity activated.

CHK1/CHK2 phosphorylate target proteins including p53 and MDM2.

MDM2 interacts with p53 targeting it for degradation so that protein does not accumulate normally.

When p53 and MDM2 are modified by phosphorylation they dissociate stabilising p53 (ie when cells are stressed/DNA damage).

p53 activates transcription of target gene trancription such as p21.

p21 protein accumulates and acts as a CDKI inhibiting cyclin A and E dependent kinases, temporarily stalling cell cycle for DNA repair to occur.

MDM2 can be actvated by as an oncogene in this pathway by amplification and increased expression (excess MDM2 would prevent p53 accumulation)

ATM/ATR, CHK1/CHK2, p53 or p21 are all TSG that can be inactivated to de-regulate this pathway.

Pathway 3: ARF, MDM2, p53, p21

Monitoring circuitry that detects abnormal mitogenic stimulation in cells caused by oncogene activation.

Explain unusual structure of INK4A gene locus encoding both p16 and p15/19 ARF

ARF transcription induced by abnormal signal

ARF interacts with MDM2 and p53 resulting in increased stability

p53 regulates target genes like p21 or apoptosis regulators pausing cell cycle or inducing apoptosis.

MDM2 could act as oncogene here as above. ARF, p53 p21 all TSG’s which can be inactivated to de-regulate pathway.

Bcl2 could be activated protecting cells from apoptosis (this possibility mentioned in earlier lecture where discussing p53 target genes).