Friday, August 29, 2014

New anti cancer role for p53

I suppose that just about everyone knows of the important role the p53 protein plays in protecting cells from becoming cancerous. The protein was identified 30 years ago and its gene (TP53) cloned soon thereafter. Whats not so widely known is just how complex the operation of p53 in protecting against cancer really is. And very recent research shows the complexity is even more than previously thought.

However, the complexity is to be expected, because evolution doesnt "design" cellular mechanisms to work in a straightforward way. The mechanisms are simply the result of about a billion years of trial and error. Being pretty and elegant was not a criterion for success.

Nature is "hairy", knowing nothing of Occams Razor, and caring even less. Simplicity is for wimps.

But one thing is clear: p53 plays a large role in preventing, or at least suppressing, the development of cancer. In many types of cancer, p53 is found to have mutations more than 50% of the time. Even if p53 isnt mutated, cancer cells generally have other p53 abnormalities, such as low levels of the protein or the presence of various factors that interfere with its activity.

Until the latest research, there have been two principal ways known in which p53 works against cancer, and several additional minor ways. The two main ways p53 has been known to act are binding to DNA as a transcription factor, and binding directly to certain proteins. And each of these mechanisms can lead to either of two main types of tumor suppression: apoptosis (cell death) and temporary or permanent suspension of the cell cycle, which is the process a cell goes through in order to divide and proliferate.

P53 is primarily a transcription factor. In this role it is found in a cell nucleus and binds to various specific DNA gene promoter regions, in order to direct transcription of the associated gene – the first step in production of proteins from a gene.

The proteins that are expressed as a result of this p53 activity can play a part in either apopotosis or cell cycle control (as well as other functions not directly related to cancer – see here, here, here). Which function is invoked depends on the type of signal that activates the p53. Among the possible conditions that may be signaled are detection of correctable or uncorrectable damage to DNA and detection of chromosome telomeres that are too short.

In addition to binding to DNA as a transcription factor, p53 is also capable of binding directly to other proteins in order to control their behavior. Mainly these proteins are involved with apoptosis, such as members of the Bcl2 family.

P53 itself is actually a family of proteins – there are at least 9 different RNA transcripts that can be derived from the TP53 gene. But one thing that each of these family members have in common is a segment, called the DNA binding domain. It is this part of the p53 that is capable of binding to either DNA or other proteins. (In general, a protein domain is a more-or-less self-sufficient component of a protein. Often the same domain appears in different members of a family of proteins.)

One indication of the importance of this p53 domain is the fact that point mutations (errors involving only a single nucleotide pair) in the part of TP53 that code for the binding domain are the only type of point mutations of p53 that are commonly found in tumors. Errors that affect portions of p53 outside of the binding domain are not associated with cancer.

Theres one more thing to note about p53s role as a transcription factor. Namely, the RNA that is transcribed under the direction of p53 is not always messenger RNA (mRNA) that will eventually code for the production of a protein. P53 can also initiate the transcription of genes that code for microRNA (miRNA), which is a single-stranded RNA molecule thats normally only 21 to 23 nucleotides in length. Over 500 different types of miRNA have been found in human cells.

MicroRNA is never translated into a protein. Instead, miRNA molecules regulate the translation of messenger RNA for many different proteins (by binding with the mRNA to prevent translation). It has been known for some time that p53 acts as a transcription factor for the miRNA family known as miR-34. It has also been learned that among the proteins regulated by miR-34 are some found in pathways that lead to apoptosis or cell cycle arrest. The net effect is that miR-34 has tumor-suppressing properties, so this is another way that p53, as a transcription factor, helps suppress tumors.

Many other miRNA molecules, on the other hand, are found at high levels in cancer cells. Such miRNAs most likely inhibit expression of tumor suppressing genes, whose proteins might otherwise control cell proliferation or migration. Weve discussed a number of miRNAs associated with cancer, mostly of the sort that promote cancer, here and here.

Nevertheless, there are miRNAs besides miR-34 that have anti-cancer effects. Three in particular are miR-16-1, miR-143, and miR-145. It has been observed that these miRNAs, and several others, are found at higher levels in cells where p53 has been activated as a result of DNA damage. (Normally, p53 formed in non-cancer cells is either quickly degraded or else inhibited by certain proteins, especially MDM2, so as not to unnecessarily promote apoptosis or cell cycle arrest. The presence of DNA damage results in the removal of these inhibitions on p53.)

It therefore appears that p53 is doing something to help produce a number of miRNAs, some of which are tumor suppressors. The curious thing, though, is that it can be shown that p53 is not a transcription factor for the genes that encode these miRNAs.

So what is it that p53 is doing instead to help produce these miRNAs? New research published in the July 23, 2009 issue of Nature answers this question – and it uncovers an entirely new mechanism through which p53 (and its binding domain, in particular) acts as a tumor suppressor. Heres the research abstract:

Modulation of microRNA processing by p53
MicroRNAs (miRNAs) have emerged as key post-transcriptional regulators of gene expression, involved in diverse physiological and pathological processes. Although miRNAs can function as both tumour suppressors and oncogenes in tumour development, a widespread downregulation of miRNAs is commonly observed in human cancers and promotes cellular transformation and tumorigenesis. This indicates an inherent significance of small RNAs in tumour suppression. However, the connection between tumour suppressor networks and miRNA biogenesis machineries has not been investigated in depth. Here we show that a central tumour suppressor, p53, enhances the post-transcriptional maturation of several miRNAs with growth-suppressive function, including miR-16-1, miR-143 and miR-145, in response to DNA damage. ... These findings suggest that transcription-independent modulation of miRNA biogenesis is intrinsically embedded in a tumour suppressive program governed by p53. Our study reveals a previously unrecognized function of p53 in miRNA processing, which may underlie key aspects of cancer biology.

To understand whats going on, its necessary to explain a few things about how miRNAs are produced. Its not a simple 1-step process of transcribing an miRNA gene into the final short piece of RNA.

There are, instead, three steps. The first step is transcription, done just as is done for any other gene. The RNA produced in this step is many nucleotides long, and is called the "primary transcript" or pri-miRNA. This pri-miRNA is then cut into smaller pieces having a hairpin shape, called pre-miRNA. The pre-miRNA, in turn, is further processed to produce the final "mature" miRNA.

The intermediate step that converts pri-miRNA to pre-miRNA is performed by a protein complex known as the "microprocessor complex" (having nothing to do with computers, of course). One of the key proteins in this complex is an enzyme called Drosha. The final step, which is performed by another enzyme called Dicer, splits the pre-miRNA apart to yield the mature miRNA.

The main contribution of p53 in this process is to facilitate the action of Drosha. It seems that, although Drosha can do the job by itself (since miRNAs are needed even if p53 isnt active), p53 helps by binding (via its binding domain) with parts of the microprocessor complex. This is indicated by the observation that mutations in the binding domain disable p53 binding to the complex, resulting in lower levels of miRNA production.

So there you have it: an essentially novel way that p53 acts as a tumor suppressor, by facilitating production, non-transcriptionally, of tumor-suppressing miRNAs.
Suzuki, H., Yamagata, K., Sugimoto, K., Iwamoto, T., Kato, S., & Miyazono, K. (2009). Modulation of microRNA processing by p53 Nature, 460 (7254), 529-533 DOI: 10.1038/nature08199

Further reading:

Protein plays three cancer-fighting roles (7/22/09) – Science News article on the research

Link between p53 and miRNA – editors summary in Nature of the research

Cancer: Three birds with one stone (7/23/09) – Nature news article on the research

Tags: p53, microRNA, cancer

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