Saturday, January 26, 2008

Cancer and Myc

Myc is a gene that has been studied for over 20 years and is found to be overexpressed in many human cancers. The protein it codes for (which for simplicity we'll also refer to as Myc) is a transcription factor, like members of the FoxO family, which means it can enable or disable the expression of many other genes. How many? The estimate is about 15% of all human genes. Since there are at least 20,000 genes, the number regulated by Myc is 3000 or more. That's a lot of leverage.

Obviously, Myc is essential for cell function or it wouldn't have so much influence. The biological functions Myc affects include cell proliferation, cell growth, apopotosis, cell differentiation, and stem-cell self-renewal. It is possible for a single transcription factor to have such varied effects because other transcription factors (coactivators or corepressors) must also be present in order to activate or repress the expression of some specific other gene. That is, the expression of any particular gene depends on the presence (or absence) of a particular set of transcription factors.

Since Myc affects the functions mentioned above, it's hardly surprising to find that Myc is overexpressed in many cancers. In such cases, the difference between a normal cell and a cancer cell is the overexpression of Myc in the latter and possibly the abnormal presence of other coactivators or corepressors. The result in a cancer cell is excessive proliferation and/or avoidance of cell death by apoptosis.

Surely you've wondered why development of cancer therapies has taken so long. A large part of the reason is that so many genes involved in cancer interact with so many other genes that have essential functions. So it's not possible to interfere with the cancer-related genes without disrupting vital biological functions elsewhere in the body.

The expression of Myc itself is triggered by signals that are usually external to the cell and normally serve to stimulate cell growth and proliferation when needed, as in lymphocyte production, normal growth, or wound healing. Such signals are called mitogens, because they can initiate mitosis. Wnt, Shh, and EGF are mitogens that can lead to Myc expression.

It is probably almost impossible to hope to combat cancer by directly affecting Myc or its related mitogens, because all of these have essential normal functions themselves. Instead, anti-cancer research needs to examine how Myc may be overexpressed or complemented in harmful ways by other transcription factors.

One promising line of research involves cancer stem cells – cells that, like normal stem cells, can proliferate and differentiate into other cell types, and that also carry cancer-causing mutations. There is now thought to be a "signature" consisting of 11 genes that may be characteristic of cancer stem cells. One of these genes has an effect on Myc:

Scientists Uncover Role Of Cancer Stem Cell Marker: Controlling Gene Expression (1/18/08)
Scientists at Jefferson's Kimmel Cancer Center in Philadelphia have made an extraordinary advance in the understanding of the function of a gene previously shown to be part of an 11-gene "signature" that can predict which tumors will be aggressive and likely to spread. The gene, USP22, encodes an enzyme that appears to be crucial for controlling large scale changes in gene expression, one of the hallmarks of cancer cells. ...

In one example, they looked at the relationship between MYC and USP22. MYC, which is among the most commonly overexpressed genes in cancer, encodes a protein that controls the expression of thousands of other genes. The scientists showed that USP22 is a critical partner of MYC and that by depleting cells of USP22, they could prevent MYC from working properly, stopping it from inducing the invasive growth of cancer cells.

It turns out that Myc affects not only 3000 or so ordinary genes, but also a number of DNA sequences that code for microRNA – and some of these microRNAs play an important role in suppressing cancer. In fact, Myc can stop the production of at least 13 microRNAs:

Silencing Small But Mighty Cancer Inhibitors (12/12/07)
Researchers from Johns Hopkins and the University of Pennsylvania have uncovered another reason why one of the most commonly activated proteins in cancer is in fact so dangerous. As reported in Nature Genetics recently, the Myc protein can stop the production of at least 13 microRNAs, small pieces of nucleic acid that help control which genes are turned on and off.

Furthermore, additional observations showed that some of these microRNAs have an inhibiting effect on cancer, a striking result in itself:
[I]n several instances, re-introducing repressed miRNAs into Myc-containing cancer cells suppressed tumor growth in mice, raising the possibility that a sort-of gene therapy approach could be effective therapy for treating certain cancers.

Since the microRNAs repressed by Myc affect many other genes, there could be thousands of other genes indirectly affected by Myc:
"This study expands our understanding of how Myc acts as such a potent cancer-promoting protein," says Mendell. "We already knew that it can directly regulate thousands of genes. Through its repertoire of miRNAs, Myc likely influences the expression of thousands of additional genes. Activation of Myc therefore profoundly changes the program of genes that are expressed in cancer cells."

More: Researchers zero in on the tiniest members in the war on cancer (12/13/07)

Myc is actually a member of a family of genes, the Myc family. Most members of the family have similar functions. Separate members undoubtedly appeared in the course of evolution from the duplication of earlier members and later mutation. One member, called N-myc, plays a role in both normal development of the retina, as well as cancers of the retina (retinoblastoma).

Recent research has shown that N-myc seems to be responsible for the surprising fact that the retinas in all vertebrates have about the same thickness, regardless of the size of the entire animal or its eyes:

Eye Cancer Gene's Role In Retinal Development Defined (1/18/08)
"A series of complex developmental processes must be carefully orchestrated for the eye to form correctly," said Michael Dyer, Ph.D., associate member in the St. Jude Department of Developmental Neurobiology. "One important aspect of this coordination is that retinal thickness be the same, irrespective of eye size. For example, the mouse eye is about 5,000 times smaller than that of the elephant eye, but the retinal thickness in these two species is comparable."

Working with mice, the researchers found that a gene called N-myc coordinates the growth of the retina and other eye structures to ensure the retina has the proper thickness necessary to convert light from the lens into nerve impulses that the brain transforms into images.

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