resisting cell death

how do cells balance their proliferation

• making new cells

• cell suicide- programmed cell death

what does p53 respond to

DNA damage

what does p53 do

• repairs damaged DNA putting on the brakes on cell function long enough to repair itself

• if the damage cant be repairs then p53 instigates apoptosis

• e.g. peeling skin following UV damage

alongside halting the cell cycle for repair what does p53 also induce

apoptosis

what does p53 inhibit

• Bcl-2

• pro-survival protein

what does p53 activate

Bax cell death

what does activation of Bax cause

causes mitochondrial outer membrane permeabilisation and release of cytochrome c into the cytosol

what does cytochrome c trigger

caspase-3 activation through formation of the cytochrome c/Apaf-1/caspase-9-containing apoptosome complex that dismantles the cell

what do normal p53 proteins do

destroys cells that have irreparable damage to their DNA

what do abnormal p53 fail to stop

• cell division

• therefore damage cells divide

• hence cancer develops

what does MDM2 gene amplification acts as

p53 loss

what viral proteins is p53 inactivated by

• adenovirus protein

• papillomavirus

• HBV

what is genomic instability

anything that disrupts the cell genome

what causes genomic instability

• loss or mutation of the DNA damage sensor protein p53

• breakdown in one or more DNA repair mechanisms

• mutagenic agents and viruses

• a combination of these factors

what do cancer cells take advantage of

increased rates of mutations in order to accumulate the mutations needed to foster tumorigenesis

what are the 2 apoptosis pathways

• extrinsic pathway

• intrinsic pathway, mitochondrial or stress pathway

which apoptotic pathway does the p53 gene promote

intrinsic pathway

what happens in the extrinsic apoptotic pathway

• cell kills itself because of signals from other cells

• death receptor pathway activates apoptosis by recruitment and activation of the pro-form of caspase-8 via the adaptors FADD, and in some cases also TRADD, at the ligated death receptors at the plasma membrane

what happens in the intrinsic apoptotic pathway

1. cell death initiated by up regulation of pro-apoprotic BH3 only members of the BCL-2 protein family

2. Bid inhibits the pro-survival protein Bcl-2, thereby unleashing the cell death effector Bax

3. activation of Bax causes mitochondrial outer membrane permeabilisation and release of cytochrome c into the cytosol

4. cytochrome c triggers caspase-3 activation through formation of the cytochrome c/Apaf-1/caspase-9-containing apoptosome complex that dismantles the cell