Sunday, December 23, 2007

FoxO transcription factors

Transcription factors are proteins that help regulate genes. This regulation may involve either enabling the expression of a gene or preventing expression. In the first case, the transcription factor is an "activator", and in the second case a "repressor".

Transcription factors perform their function by binding to a particular portion of DNA that is specific to a given gene. When bound to the appropriate DNA segment, a transcription factor affects gene expression by either facilitating (activator) or inhibiting (repressor) the operation of RNA polymerase in transcribing the affected gene into messenger RNA. Usually more than one transcription factor must be present to affect gene transcription, and additional proteins (called "cofactors") may also be required.

To make things even more interesting, transcription factors usually affect multiple genes, which may be otherwise unrelated to each other.

A particularly important family of related transcriptions factors comprises what are called "forkhead box" proteins, or Fox proteins, for short. (The name refers to a sequence of 80 to 100 amino acids that are part of the protein and bind to DNA, and which was originally discovered in fruit flies (Drosophila).)

Among the genes that Fox proteins are involved with are genes related to cell growth, proliferation, differentiation, longevity, and embryonic development. So there are Fox proteins that are important for things like cancer and stem cells – and thus it's quite useful to know about them.

An important subfamily of Fox proteins are the FoxO proteins, and we'll discuss some recent examples in this note.

To begin with, perhaps the most recent example is this:

Molecular Signal That Helps Muscle Regenerate Discovered (12/19/07)
Muscle regeneration after injury is complex and requires a coordinated interplay between many different processes. Key players in regeneration are muscle stem cells, so-called satellite cells. They divide and produce many new muscle cells to fix the damage incurred by injury. A crucial regulator of muscle function and repair is a signalling molecule called calcineurin. It is activated by injury and controls the activity of other key proteins involved in differentiation and the response to damage.

It turns out that calcineurin works by inhibiting FoxO.
Using sophisticated molecular techniques, the scientists revealed that calcineurin accomplishes its effect on muscle by inhibiting another protein called FoxO. FoxO is a transcription factor, a protein that plays a crucial role in skeletal muscle atrophy through the induction of genes involved in cell cycle repression and protein degradation. Suppressing the effects of FoxO, calcineurin ensures that proliferating cells stay alive and keep dividing to produce enough cells to repair muscle damage.

In this case, the normal function of FoxO is to inhibit cell proliferation (as a check on cancer), but this needs to be bypassed (temporarily) to enable muscle regeneration.

This result follows the discovery a few months earlier of the way a specific FoxO protein (FoxO1) cooperates with another important developmental protein (Notch) to control muscle cell differentiation:

Building Muscle Requires Foxo1 (8/25/07)
The mechanisms by which Foxo proteins regulate metabolism are relatively well characterized. However, little was known about the mechanisms by which these same proteins regulate cellular differentiation.

New data generated by Domenico Accili and colleagues at Columbia University, New York, now indicates that Foxo1 cooperates with Notch to control muscle cell differentiation in vitro.

Overexpression of either a constitutively active form of Foxo1 or a constitutively active form of Notch was found to inhibit the in vitro differentiation of a mouse myoblast cell line.

Note that the preceding alludes to the involvement of FoxO proteins in regulation of metabolism. This comes about because they affect the insulin signaling pathway, and hence also glucose and lipid metabolism.

This function is what allows yet another well-known protein, mTOR, to play a role in "metabolic syndrome" – a group of disorders that includes insulin resistance, heart disease and high lipid levels. (mTOR is short for "mammalian target of rapamycin". It's a protein kinase that modifies other proteins by phosphorylation.) The same mechanism appears relevant also to the "Atkins diet" and the effects of calorie restriction.

Fly Genetics Reveal Key Workings Of Atkins Diet (8/8/06)
Using fruit flies bred with a newly created mutant form of the gene TOR (short for target of rapamycin), Oldham and his colleagues were able to determine how the TOR pathway interacted with other important regulators of insulin, glucose and lipid metabolism.

TOR is an ancient gene, found in nearly all animal and plant cells. The researchers discovered that their new mutant fly reduced TOR function, allowing them to observe what happens when TOR's influence is removed.

Reductions in TOR function lowered glucose and lipid levels in the body. They also blocked the function of another important insulin regulator, a factor called FOXO, which is known to be a critical mediator of insulin signals and therefore glucose and lipid metabolism.

As if all that weren't enough, FoxO proteins are also involved with cancer and stem cells:

Gene Knockouts Reveal FoxOs' Vital Functions In Cancer Defense, Health Of Stem Cells (1/25/07)
In an elegant, multiple-gene knockout experiment, a team of Boston scientists has discovered that a trio of molecules, called FoxOs, are fundamentally critical in preventing some cancers, maintaining blood vessel stability, and in keeping blood-forming stem cells healthy. ...

The researchers at Brigham and Women's found that mice engineered to lack genes for the FoxO1, FoxO3, and FoxO4 molecules had serious blood abnormalities. Without the FoxO gene-regulating molecules, the rodents' blood stem cells -- master cells that give birth to working blood cells while also renewing themselves -- divided too fast and "burned out." ...

In the companion paper, lead author Ji-Hye Paik, PhD, of Dana-Farber and colleagues from the DePinho lab report that the three FoxO molecules, known as transcription factors, normally function as tumor suppressors that override maverick cells threatening to grow too fast and form tumors. When FoxOs are eliminated, it may allow cancer to develop.

And even that's not the end of it. FoxO proteins are also involved in the increased levels of inflammation often associated with the aging process. (This phenomenon has been tagged with the neologism "inflammaging".) It has been hypothesized that inflammaging results from the effect of phosphorylated FoxO on another notorious transcription factor, NF-κB (which is heavily involved in inflammation). Some of the effects of calorie restriction may also be due to FOXO phosphorylation. Reference: Restricting inflammaging (11/12/07)

FoxO is also regulated (as is P53) by SIRT1 – so this is yet another relationship to calorie restriction. Reference: Unlocking the Secrets of Longevity Genes

Additional references (for the seriously interested):

An AMPK-FOXO pathway mediates longevity induced by a novel method of dietary restriction in C. elegans.

Ageing: When Less Is More

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