My apologies for not getting this next post up faster – I was preparing for the conference that I’m currently attending. I have actually never attended a scientific conference before, but I’ll spare you the details of such an adventure until it is over. In the next four days, I will attend more talks than I can really handle, I’ll present my own research (as I was invited to give a talk) and I’ll unroll the poster that is currently taking up space in the backseat of my car. Yes, a poster. Just like your second grade science fair…
Lesions within stratified epithelia tell a doctor that something is wrong. In the case of cervical abnormalities, it often means the cells within the lesion are infected with HPV.
What does the virus do once it is inside your cell? How does it make the cell stop differentiating? How do those things lead to cancer?
Okay; one step at a time.
Let’s start with something called “the cell cycle.”
Cells divide. I think most people knew that and I bet, if some of you reach far back, you’ll remember that the process a cell goes through to divide is called mitosis. Mitosis is actually only one act in a four act cellular play. The others are called G1, S, and G2. The fourth, mitosis, is called M.
Pretend you are looking at a cell that is just about to enter mitosis. Keep watching. As mitosis proceeds, you watch as the one cell splits down the middle to create two smaller cells (called daughter cells). The two daughter cells will now enter a stage of the cell cycle called G1, where G stands for growth. This is a time for the cell to build itself up in size, make new proteins, perform its duties, etc.
Eventually, a signal will come that tells the cell is has to prepare itself to divide again. At this point, the cell will pass out of G1 and enter the S phase, where S stands for synthesis. What happens now? The entire DNA molecule within the cell is faithfully replicated. At the end of this stage, the cell will have two complete DNA molecules: one for each daughter cell.
Following the S phase, the cell enters another growth phase, called G2. It grows a bit more and prepares itself to split into two halves.
Once the cell gets the go ahead to split, it enters mitosis and two daughter cells are born. These two daughter cells then enter G1 and the cycle repeats.
It is fair to mention that for any being to live a healthy life, the cell cycle must be protected. A whole range of checkpoints exist that the cell must pass correctly before it is allowed to move on. If anything is amiss, the cell won’t divide and will instead stop to fix problems or, in extreme cases, kill itself. The cell cycle is no joke.
This cycle is summarized in Figure 19.1.
I’m sure you are wondering what this has to do with HPV. Let’s focus on three parts.
One: Why does the HPV target basal cells and not other cells of the epithelia?
Remember that I told you in the last post (HPV: Transitions) that the cells sitting at the very top of the epithelia can’t divide anymore. If the cells aren’t dividing, then they aren’t passing from G1 to S to G2 to M anymore. Instead, these cells exist in a static state known as G0. However, the basal cells are still dividing and they are still passing through the phases of the cell cycle.
This is important information for a virus. The main goal of a virus is to replicate itself (Spanish Influenza, Part 2). In order for the virus to replicate, it needs its DNA replicated, which can only happen if the cell it gets inside will pass through the S phase.
Those upper protective cells? No S phase them.
Those basal cells? Excellent!
Two: What happens after the virus infects the basal cells?
I’d first recommend reviewing the post “Spanish Influenza, Part 2” to remember what is involved with a viral infection: the virus “infects” a cell by getting inside, hijacks the cell’s machinery (which had been making cellular proteins) to start making viral proteins, and the cell begins to fill with freshly made virus particles.
HPV’s genome also encodes two proteins not involved (or not directly involved) in making new virus particles: E6 and E7. Together, these two proteins work to mess up the cell cycle of basal cells. In the shortest and most plain English possible, this is how they work:
I told you that the cell must receive some signals and pass certain checkpoints to exit G1 and enter the S phase. These signals are highly regulated and only happen when the timing is correct. However, if E7 is around, it mimics these signals and tells the cell it is fine to enter the S phase. It acts as a complete charlatan and the cell, while wary, follows E7’s instructions.
Luckily, the cell isn’t dumb. It has safeguards in place to protect it from being unnaturally forced from one phase of the cycle to another. E7 does raise the suspicion of the cell’s defenses and the commander and chief of the army, a little protein called p53! (Cancerous Mutational Problems) In response to E7, p53 would normally tell the cell something was up and to halt operations. E6, however, is waiting and deals a deathblow to p53 to remove it from the game.
So what do we have now? A cell that can replicate (E7 ensures that) and divide (E6 ensures that) without anything making sure it is doing so properly. These actively dividing cells are moving all over the epithelia and leading to the green cells from Figure 18.1 (HPV: Transitions post) and visible lesions that your doctor can see.
I’m sure you can guess that this spells trouble. Lots of trouble.
Three: How does this lead to cancer?
The cell cycle ensures fidelity in replication of cells, especially in the DNA. Cancer comes from many places, but one of which is mutations in the DNA (Cancerous Mutational Problems post). Without p53 or proper signals for the S phase, the DNA in an HPV-infected cell will quickly rack up mutations. It’s only a matter of time before one of those mutations leads to a problem.
There are other ways, as well, but that is beyond the scope of this post. I just wanted to show how the virus is setting up infected cells for big time failures. It’s like having a spy in your company or someone spilling poison into your nicely baked cupcakes. Sooner or later, there’s going to be a big BIG problem…
Cell cycle – the series of phases a cell goes through that leads to cell division
Mitosis – the phase of the cell when it actually splits into two smaller cells
G1 – first growth phase of the cell cycle
S – synthesis phase of the cell cycle, DNA is faithfully replicated
G2 – second growth phase of the cell cycle
M - mitosis
Daughter cells – mitosis splits one cell into two; these two new cells are called daughter cells
G0 – if a cell has reached a point where it will no longer need to divide, but its function is still needed, the cell will enter a state called G0 – a permanent G phase that can’t lead to the S phase.
References
Suryadinata et al. Bioscience Reports (2010) 30, pgs 243 – 255
Doorbar, J. Journal of Clinical Virology (2005) 32, pgs S7 – S15
Huibregste JM, Scheffner M, Howley PM (1993) Localization of the E6-AP Regions that Direct Human Papillomavirus E6 Binding, Association with p53, and Ubiquitination of Associated Proteins. Molecular and Cellular Biology 13: 4918 – 4927
Munger K, Howley PM (2002) Human papillomaviruses immortalization and transformation functions. Virus Research 89: 213 - 228
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