L10 - HPV (2) Flashcards
What are the 3 factors that affect HPV pathogenicity?
viral oncoproteins - deregulate host signalling processes
Host genetics - ability to combat HPV
Environmental factors - predispose towards cancerous phenotype
Do low risk HPVs immortalise keratinocytes?
NO
What is the major transforming protein?
E7
Properties/actions of E7 protein?
NOT enzymatic
function by binding to CELLULAR FACTORS - pRb, p107, p130
tumour suppressors
How does E7 bind to tumour suppressor proteins?
LXCXE motif
How dot he Rb family of proteins control the G1-S phase?
regulate activity of E2F family TFs
How does E2F convert from a transcription repressor to a transcriptional activator by E7?
E7 interats with pRb by LXCXE motif
ubiquitin ligase complex made
E2F is released from repression
drives cell into S phase
What is the major consequence of efficient targeting of pRb by E7?
increased p53
need to neutralise this to allow proliferation
features of the E6 oncoprotein?
no enzymatic activity
interacts with MULTIPLE HOST FACTORS
What is the most studied E6 interaction?
HOST E3 ubiquitin ligase
how does protein ubiquitination involving host E3 occur?
enzymes cascade - E1, E2, E3 cascade
E3 adds Ub to target protein
7 lysines within Ub protein
depending on which lysine - different physiological outcome
K48 - degradation, other K63 - cell signalling
What does K48 linked Ub chains do?
tageted for degradation by proteasome
What does K63 linked Ub chains do?
cell signalling, NOT degradation
How does E6 mediate the degradation of p53?
in HPV-infected cell - E6 can bind p53 by binding to the Ub ligase E6-AP
anti-proliferative impact of p53 reduced
What does p53 usually bind to?
MDM2
adds a K48 linked chain
What do High risk HPV E6 proteins have at their extreme C-terminus?
PDZ-binding motif (PBM)
What are PDZ domains?
protein-protein interaction motifs
found in host cell proteins associated with cell polarity & signalling
many= tumour suppressors, oncogenes
Is PDZ binding motif found in E6 proteins in non-cancerous HPV?
NO!!
Why are PDZ protein important?
hyperplasia/tumour formation is dependent on ability to bind to PDZ proteins
What dos E6 do to the STAT3 transcription factor?
activates
usually inactive in cytoplasm
translocates into nucleus serving as TF
drives expression of cyclins and suppresses anti-survival proteins
How hyperactive is STAT3 in cancer HPV types?
hyperactive in 70% of types
Features of E5?
hydrophobic membrane protein
many interacting partners
What does E5 maintain?
maintains EGFR expression & signalling differentiating signals
What are the reversible stages of epithelium changes i HPV
normal CIN I
CIN I CIN II
CIN II CIN III
CIN III CIS
What are the irreversible stages of epithelium changes?
CIS —> Invasive carcinoma
What gene is often inactivated?
E2 ORF
E6/E7 expression increases = proliferation
What happens when HPV integrates into the chromosomes?
STOPS producing virus
What are the 2 types of HPV DNA status?
Episomal (low risk)
Integrated (high risk and medium risk too)
Risk factors for HPV?
High number sexual partners
age at first intercourse
smoking
oral contraceptive use
male partner sexual behaviour
