Sharrocks- Cancer

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Tumour suppressors are...

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recessive so both alleles must be lost to have an effect

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Oncogenes are...

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dominant so only one allele must be lost to have an effect

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Syndrome associated with p53 mutations

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Li Fraumeni

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Tumour suppressor - inhibits cdks e.g.

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p16

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RB and p53 stop at which phase of cell cycle

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G1-S

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Proto-oncogenes stimulate at which phase of cell cycle?

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Go-1

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p53 is a DNA binding transcription factor that exists as a...

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tetramer

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Which c-terminal domain is critical to p53 function

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Oligomerisation domain

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p53 binds to DNA via the

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DNA binding domain

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When p53 acts as a repressor it binds to DNA...

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indirectly via a TF

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When p53 binds indirectly to a TF it represses transcription by

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inhibiting RNA polymerase II

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Examples of genes that p53 represses are...

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c-myb, Bcl-2, Bcl-x, PCNA, DNA polymerase alpha

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When p53 acts an activator it binds to DNA...

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directly to DNA

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Examples of genes that p53 activates include...

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p21, Bax, PUMA, NOXA

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Active protein in HPV

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E6

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Active protein in SV40

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Large T antigen

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E6 and the Large T antigen

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inactivate p53

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RB levels within the cell cycle

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remain constant

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RB is a tumour supressor so it blocks cell cycle at phase

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G1-S

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RB forms a complex with and inactivates

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E2F

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RB-E2F recruit

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HDAC

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E2F (1-7) form heterodimers with

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DP (1-3)

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Protein in HPV that binds to RB

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E7

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E7 binds to RB in the

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binding site pocket

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RB

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found in most cells

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p53

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expressed at low levels

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Phosphorylation by * of RB inactivates it

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cdk4/cyclin D/E

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RB represses gene expression by

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HDACs and BRG1

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BRG1 functions by

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remodelling ATPases

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E2F can displace RB-HDAC and

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recruit HAT

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An example of a HAT

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CBP

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CBP +/- mice

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develop leukaemia

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CBP translocations are common in cancer e.g.

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AML: MOZ-CBP fusion

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PDGF and EGF are

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RTKs

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Ser/Thr Kinases are

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MAPKs, Raf-1

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Thr/Tyr kinases are

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MEKs

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PDGF has 3 dimers types

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AA, BB, AB

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Subunit in PDGF that can become a proto-oncogene

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B

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JNK induces proliferation through

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AP-1

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JNK induces apoptosis through

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Tumour supressors

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p38 induces

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apoptosis

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AP-1 stands for

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activating protein 1

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AP-1 is a...

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dimer

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AP-1 dimer is made of

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Jun and Fos

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Fos-Fos

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Does not exist

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Jun subtypes include:

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c-, -B, -D

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Fos subtypes include:

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c-, -B, Fra1 & 2

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Fos and Jun are

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bZIP proteins

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c-Fos and c-Jun bind to DNA

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at palindromic sites

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At DNA Fos/Jun has a higher * than Jun/Jun dimers

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Affinity

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Fos/Jun activate transcription by activating RNA pol II and

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CBP

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c-Fos protein forms a dimer due to

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leucine rich alpha helix

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Osteosarcomas contain

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v-fos oncogenes

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v-Fos increases gene expression due to

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long terminal repeats

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V-fos is always

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in the nucleus

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When v-fos loses its delta-domain * can't bind

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HDAC3

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What phosphorylates c-jun at Serine 243

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MAPK

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Phos at Ser243 on c-jun primes for

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GSK3

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GSK3 phosphorylation of c-Jun means

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E3 ligase will bind

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Mutated Ser243 on v-jun means

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E3 ligase can't bind