L10 - HPV (2)

Question 1

What are the 3 factors that affect HPV pathogenicity?

Answer 1

viral oncoproteins - deregulate host signalling processes

Host genetics - ability to combat HPV

Environmental factors - predispose towards cancerous phenotype

Question 2

Do low risk HPVs immortalise keratinocytes?

Answer 2

NO

Question 3

What is the major transforming protein?

Answer 3

E7

Question 4

Properties/actions of E7 protein?

Answer 4

NOT enzymatic

function by binding to CELLULAR FACTORS - pRb, p107, p130

tumour suppressors

Question 5

How does E7 bind to tumour suppressor proteins?

Answer 5

LXCXE motif

Question 6

How dot he Rb family of proteins control the G1-S phase?

Answer 6

regulate activity of E2F family TFs

Question 7

How does E2F convert from a transcription repressor to a transcriptional activator by E7?

Answer 7

E7 interats with pRb by LXCXE motif

ubiquitin ligase complex made

E2F is released from repression

drives cell into S phase

Question 8

What is the major consequence of efficient targeting of pRb by E7?

Answer 8

increased p53

need to neutralise this to allow proliferation

Question 9

features of the E6 oncoprotein?

Answer 9

no enzymatic activity

interacts with MULTIPLE HOST FACTORS

Question 10

What is the most studied E6 interaction?

Answer 10

HOST E3 ubiquitin ligase

Question 11

how does protein ubiquitination involving host E3 occur?

Answer 11

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

Question 12

What does K48 linked Ub chains do?

Answer 12

tageted for degradation by proteasome

Question 13

What does K63 linked Ub chains do?

Answer 13

cell signalling, NOT degradation

Question 14

How does E6 mediate the degradation of p53?

Answer 14

in HPV-infected cell - E6 can bind p53 by binding to the Ub ligase E6-AP

anti-proliferative impact of p53 reduced

Question 15

What does p53 usually bind to?

Answer 15

MDM2

adds a K48 linked chain

Question 16

What do High risk HPV E6 proteins have at their extreme C-terminus?

Answer 16

PDZ-binding motif (PBM)

Question 17

What are PDZ domains?

Answer 17

protein-protein interaction motifs

found in host cell proteins associated with cell polarity & signalling

many= tumour suppressors, oncogenes

Question 18

Is PDZ binding motif found in E6 proteins in non-cancerous HPV?

Answer 18

NO!!

Question 19

Why are PDZ protein important?

Answer 19

hyperplasia/tumour formation is dependent on ability to bind to PDZ proteins

Question 20

What dos E6 do to the STAT3 transcription factor?

Answer 20

activates

usually inactive in cytoplasm

translocates into nucleus serving as TF

drives expression of cyclins and suppresses anti-survival proteins

Question 21

How hyperactive is STAT3 in cancer HPV types?

Answer 21

hyperactive in 70% of types

Question 22

Features of E5?

Answer 22

hydrophobic membrane protein

many interacting partners

Question 23

What does E5 maintain?

Answer 23

maintains EGFR expression & signalling differentiating signals

Question 24

What are the reversible stages of epithelium changes i HPV

Answer 24

normal CIN I
CIN I CIN II
CIN II CIN III
CIN III CIS

Question 25

What are the irreversible stages of epithelium changes?

Answer 25

CIS —> Invasive carcinoma

Question 26

What gene is often inactivated?

Answer 26

E2 ORF

E6/E7 expression increases = proliferation

Question 27

What happens when HPV integrates into the chromosomes?

Answer 27

STOPS producing virus

Question 28

What are the 2 types of HPV DNA status?

Answer 28

Episomal (low risk)

Integrated (high risk and medium risk too)

Question 29

Risk factors for HPV?

Answer 29

High number sexual partners

age at first intercourse

smoking

oral contraceptive use

male partner sexual behaviour