So what is going on with human papillomavirus? So how does it cause cervical cancer?
We've seen this diagram before where normal growth factors cause the transition from
G1 to S that requires the activation of cyclin D using cyclin-dependent kinase 4 or 6 and
cyclin-E with CDK2 and that's basically going to hyperphosphorylate our E2R retinoblastoma
gene product, RB protein. And when it hyperphosphorylates, we release E2F and we can
get now progression through the G1S cell cycle block. Okay, that's what normally happens.
What happens in the setting of HPV? Well, in HPV one of the proteins that is made is called
a viral protein E7 and it promotes increased degradation of the RB protein. Oh dear.
Now, I don't have enough RB to be the block on E2F and that E2F now is free to sit on its
transcription activation sites and transcribe off a whole bunch of new proteins and genes.
Okay, so that's one of the ways that the viral genome can impact cell cycle regulation.
So we have, again, the viral E7 protein will cause the degradation of RB which will get rid
of that transcriptional block and in fact will give you a lot of unregulated E2F transcription.
Human papillomavirus also causes a degradation of p53 or again remember from this
diagram that you've seen previously that DNA damage is sensed and when it's sensed we
increase the expression of p53. That upregulation of p53 causes then in turn transcriptional
upregulation of p21 to turn off the cell cycle progression, Gadd45 to also do DNA repair
and increases BAX and other apoptotic change to cause apoptosis. Okay, I already told
you what happens here. The virus E6 protein and HPV will cause the increased inactivation
of p53. It's as if we no longer have p53 anymore. Oh my goodness that means then that
we don't affect repair, we don’t stop cell cycle progression and the cells do not undergo
apoptosis. So by having the virus express both E6 and E7 to degrade p53 and RB, we are
getting cellular proliferation and as the cells proliferate every cell cycle has the potential
to have some accumulated mutations that get locked in. And especially in the absence of
p53 there's going to be instability, we're going to get more and more and more mutation
so eventually we get carcinoma in situ.