Comb jellies, again

Comb jellies were in the news back in April, and I discussed that here. They're a lot like jellyfish, only different. In particular, they are now thought to be the closest living relatives of the earliest animals on this planet.

The most recent news is that, although the bodies of these animals appear primitive, their genetic machinery has interesting resemblances to that of more modern animals, including humans.

Genes key to the development of modern animals' body plans show up in primitive-looking comb jellies (6/6/08)

No one suspected that the primitive comb jellies — watery, rotund and nearly invisible sea creatures — would rely on an intricate interplay of genes to design their rudimentary bodies. Yet researchers got a surprise when they looked at the comb jelly’s genes. Scientists found pattern-making genes that, in most animals, plot out the position of the head, brain, limbs and rear ends during development. These “homeobox” genes turned on in a specific pattern in the comb jellies, even though these ancient sea creatures are headless, brainless, limbless and rear end–less, scientists show in the June Development Genes and Evolution.

Homeobox genes are genes that have specific genetic code sequences. The sequences code for portions of proteins (called homeodomains) that are in turn able to bind to DNA, so that the proteins act as transcription factors. These transcription factors are especially important in the process of embryonic development, as they determine the overall body plan of the organism. Homeobox genes aren't unique to animals. They're also found in plants and fungi.

However, although comb jelly homeobox genes are similar to those of other animals, and they have functions in comb jellies that are vaguely similar to their functions in other animals, there are important differences too:

Certain genes expressed in the mouths of comb jellies and in the heads of other animals could indicate that the comb jellies’ mouths correspond to the front-end of all animals (except for amorphous sponges), Martindale says. And it implies that the mouth region of an ancestral headless animal is in the same area where the first head eventually arose. Although comb jellies are using the same basic toolkit as other animals, they might be doing so in an entirely different way, Martindale says. Genes involved with limb formation in other animals were expressed at seemingly random points along the comb jellies’ throat-like pharynx, for example.

“Mice, flies and even cnidarians [jellyfish and sea anenomes, mainly] seem to be built on the same basic plan, but the sponges and comb jellies don’t fall into that mold,” Martindale says.

Tags: Ctenophora, homeobox

Wnt signaling

We've discussed Wnt signaling a couple of times before, here, and here.

Wnt refers to a family of proteins now numbering perhaps 20 or more, which have been found in a wide range of multicellular animals, from fruit flies, to fish, to mice and humans. Wnt proteins carry messages between cells, and are especially important in embryogenesis. They are known to play a large role in the control of stem cells and regeneration of body parts (in species where this occurs). In mammals, including humans, Wnt signaling, when it malfunctions, also seems to be involved in many types of cancer, degenerative diseases of aging, and other aging-related problems such as insulin resistance. It may be possible to ameliorate a number of these disease conditions once we have a better understanding of the details of Wnt signaling.

The "Wnt signaling pathway" refers to a sequence of proteins that, in the presence of earlier members of the pathway, change in behavior to affect proteins later in the pathway. The pathway begin when a Wnt protein (secreted by a nearby cell) binds to a cell surface protein, such as the whimsically-named Frizzled. Various other proteins in the pathway then interact, and eventually result in the build-up of a protein called β-catenin, which enters the cell nucleus, where it combines with various transcription factors to affect gene expression.

The name "Wnt" originates from the realization that two genes discovered earlier were homologous – the "wingless" gene in fruit flies (which, when mutated, yields flies without wings), and the Int genes found in mouse tumors.

Although Wnt genes and proteins have now been studied for nearly 20 years, the pace of discovery continues to increase. This is because of the large number of very interesting processes heavily influenced by Wnt signaling – from proliferation and differentiation of stem cells to embryonic development, regeneration of body parts, cancer, and degenerative diseases of aging.

The following summaries of research reports from just the past half year or so will give a buffet-style sample of Wnt-related investigations.

Carbohydrate Regulates Stem Cell Potency (2/1/08)

Embryonic stem cells are characterized by an ability to continually self-renew, but also to give rise to any adult cell type. Stem cell renewal is driven by several external signaling proteins and growth factors, including Wnt, FGF (fibroblast growth factor), and BMP (bone morphogenetic protein). In particular, Wnt signaling stimulates β-catenin to produce the transcription factor Nanog, which maintains pluripotency. However, the ability of these proteins to attach to stem cell surface proteins in order to induce a response seems to depend on the presence of a carbohydrate molecule called heparan sulfate (HS). Stem cells were found to reproduce less frequently but differentiate more frequently in proportion to experimental inhibition of HS production.

Beta-catenin Gradient Linked To Process Of Somite Formation (12/27/07)

In a developing vertebrate embryo somites are masses of a type of tissue (mesoderm) that will eventually develop into such adult tissue types as skeletal muscle and vertebrae. This research on mouse embryos demonstrates the importance of β-catenin as the principal mediator of the Wnt-signaling pathway, in the process of somite formation. In particular, there is a gradient in levels of β-catenin found in cells of the presomitic mesoderm (PSM), and this gradient is critical in regulating mesoderm maturation. This leads to the development of the characteristic vertebral column in embryos of vertebrate animals.

Certain Diseases, Birth Defects May Be Linked To Failure Of Protein Recycling System (12/20/07)

The Wnt signaling protein, like other proteins, is produced in the nuclei of certain cells, and it must be transported to the cell surface, so it can be secreted into the extracellular environment to regulate the growth of tissues during (and after) embryonic development. Another protein, called Wntless (Wls), acts as a cargo container for Wnt, and plays a key role in the transport process. Another protein, called Vps35, which makes up an important part of the "retromer complex", is responsible for moving empty Wls molecules (like freight cars) to where they are needed in the cell. But mutated Vps35 proteins can fail to perform their function, and consequently lead to the failure to transport Wnt out of the cell where it has been produced.

Grape Powder Blocks Genes Linked To Colon Cancer (11/14/07)

Previous research has found that the Wnt signaling pathway is linked to more than 85 percent of sporadic (i. e. not caused by a hereditary defect) colon cancers. Additionally, in vitro studies have shown that resveratrol is capable of blocking the Wnt pathway. The present research showed that in some colon cancer patients who consumed grape powder (which contains resveratrol and possibly other active ingredients), Wnt signaling in biopsied colon tissue was significantly reduced.

Odd protein interaction guides development of olfactory system (10/29/07)

The olfactory system of fruit flies has been shown to develop abnormally when the signaling protein Wnt5 is absent. However, if large amounts of Wnt5 but no Wnt5 receptors called "derailed" are present, development is even more abnormal. Specifically, structures called glomeruli in fruit fly antennal lobes (which are analogous to human olfactory bulbs) grow abnormally when Wnt5 is absent. But if Wnt5 is present in large amounts and there are no derailed receptors, malformed glomeruli develop in locations where they should not be.

Cilia: Small Organelles, Big Decisions (10/3/07)

Research into the development of zebra fish (a favorite of developmental biologists) has shown that organelles called cilia in the cells of developing embryos play a large role in the transduction of Wnt signaling proteins that guide the development process. By blocking the production of three proteins used by cilia, researchers were able to disrupt proper balances in the interpretation of Wnt signals, resulting in developmental defects.

New Insights into the Control of Stem Cells: Keeping the Right Balance (9/15/07)

The Wnt signaling pathway plays a crucial role in embryonic development, cell growth (proliferation), and maturation of cells into specialized cells (differentiation). It is also an important regulator of stem cells. An interaction between Wnt signaling and tyrosine kinases enables the proliferating cells to mature into specialized (differentiated) cells. Normally this interaction strikes a proper balance between proliferation and differentiation. Cancers, such as breast and colon cancer, result when the interaction gets unbalanced. In 90% of human cancers the tumor suppressor APC (adenomatous polypolis coli), one of the core components of the Wnt pathway, is deregulated. This results in excessive amounts of β-catenin, which triggers the onset of breast and colon cancer when it gets into the cell nucleus and affects gene expression.

Reactivating A Critical Gene Lost In Kidney Cancer Reduces Tumor Growth (8/15/07)

Studies of an important tumor-suppressor protein, sFRP-1 (secreted frizzled-related protein 1), in clear cell renal cell carcinoma, the most common type of kidney cancer, may reveal a means to defeat the cancer. sFRP-1 was found to control 13 tumor-promoting genes along the Wnt signaling pathway, which has been linked to a number of cancers, especially colon cancer. Several close relatives of sFRP-1 are also known to affect at least 20 Wnt-related proteins, and up-regulation of members of the sFRP-1 family may be an effective way to control cancers linked to Wnt signaling. In one experiment, increasing sFRP-1 expression in human renal cancer cells was effective, and Wnt regulated oncogenes, such as c-myc, were suppressed compared to untreated cells.

Why Aging Muscles Heal Poorly (8/9/07)

Stem cells normally found in muscle tissue are responsible for repair to muscles damaged by injury or age-related degeneration. But in aged muscle tissue, stem cells tend to produce scar-tissue cells called fibroblasts, instead of normal muscle cells (myoblasts). The overproduction of fibroblasts is a condition known as fibrosis. New research shows that it isn't the age of the muscle stem cells that is the problem, but rather the age of the cellular environment itself, including blood supply to the tissue. The malfunction appears to be a problem with Wnt signaling in the aged environment rather than with the actual stem cells. Muscle stem cells from young mice exhibited the same problems when exposed to an enviroment from older animals.

Related research found that Wnt signaling increased, with detrimental effect, due to age-related deficiency of a hormone called klotho. Klotho seems to inhibit Wnt signaling, and also has some control over insulin sensitivity. However, production of klotho seems to decline with age, possibly leading to age-related problems such as cancer, arterial disease, and insulin resistance.

Not A Relay Race, But A Team Game: New Model For Signal Transduction In Cells (6/27/07)

Details of the inner workings of the Wnt signal transduction process have remained incomplete, but are gradually coming into focus. Member of the Wnt family of proteins may dock with a variety of cell-surface proteins, including LRP6 (low density lipoprotein receptor-related protein 6) and members of the family of G protein-coupled receptors known as Frizzled. After the docking, a signaling cascade is triggered that transmits molecular messages via the cytoplasm to the nucleus. This research shows that the first step after docking involves large protein complexes formed from proteins already known to be part of the signaling pathway, such as phosphorylated LRP6, axin, and Dishevelled (Dvl).

Further reading:

The Wnt Homepage

Regeneration for Repair's Sake

The answer is blowing in the Wnt

Miller on Wnt and Klotho

A hazy shade of Wnt

Tags: Wnt, embryogenesis, stem cells, signal transduction, cancer, developmental biology, aging

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.

Tags: cancer, Myc, microRNA