Monday, March 17, 2008

Embryonic stem cells and Klf4

There's now some additional information on one of the transcription factors written about here, which are able to reprogram adult skin cells into embryonic stem cells. To review, one of the teams responsible for this research used Oct3/4, Sox2, c-Myc, and Klf4 for the reprogramming, while another team used Oct3/4, Sox2, Nanog and Lin28.

Of the transcription factors in the first list, all but Klf4 have been well-studied. So it is of some interest to know more about Klf4, and why it seems to be somewhat less essential than the others.

Some of the interesting details are reported on here: Molecular Alliance That Sustains Embryonic Stem Cell State Identified.

Klf4 is normally active in real embryonic stem cells. To investigate the role Klf4 might be playing in the reprogramming of skin cells, the researchers investigated embryonic stem cells that had been artificially depleted of Klf4. To their surprise, the team found that the cells maintained their pluripotency.

The question then was how to explain this. What was found is that two closely-related transcription factors – Klf2 and Klf5 – took over the role of Klf4:
"Most important, the data showed that the other Klfs were bound to the target sites when one of them was depleted." said Dr. Ng. "These Krüppel-like factors form a very powerful alliance that work together on regulating common targets. The impact of losing one of them is masked by the other two sibling molecules."

This family of transcription factors, called Kruppel-like factors, gets its name from a homology to the Drosophila Krüppel protein. Members of this family have been studied for their roles in cell proliferation, differentiation and survival, especially in the context of cancer.

Interestingly enough, according to the research press release,
Klfs were found to regulate the Nanog gene and other key genes that must be active for ES cells to be pluripotent, or capable of differentiating into virtually any type of cells. Nanog gene is one of the key pluripotency genes in ES cells.

"We suggest that Nanog and other genes are key effectors for the biological functions of the Klfs in ES cells," Dr. Ng said.

"Together, our study provides new insight into how the core Klf circuitry integrates into the Nanog transcriptional network to specify gene expression unique to ES cells.

Nanog, of course, is one of the transcription factors in the set of transcription factors which was found to be an alternative, for reprogramming adult cells, to the set that contained Klf4.

The Nanog protein, too, is known to be critically important in pluripotent stem cells. It is a homeobox transcription factor that appears to play an essential role in self-renewal of undifferentiated embryonic stem cells. It also appears to be connected with cancer, because (according to Wikipedia) "It has been shown that the tumour suppressor p53 binds to the promoter of NANOG and suppresses its expression after DNA damage in mouse embryonic stem cells. p53 can thus induce differentiation of embronic stem cells into other cell types which undergo efficient p53-dependent cell-cycle arrest and apoptosis."

The connection of Klf proteins with cancer is not only through Nanog. According to Wikipedia, "Klf4 also interacts with the p300/CBP transcription co-activators." The closely-related p300 and CBP "interact with numerous transcription factors and act to increase the expression of their target genes." And they too are involved with cancer:
Mutations in the p300 gene have been identified in several other types of cancer. These mutations are somatic, which means they are acquired during a person's lifetime and are present only in certain cells. Somatic mutations in the p300 gene have been found in a small number of solid tumors, including cancers of the colon and rectum, stomach, breast and pancreas. Studies suggest that p300 mutations may also play a role in the development of some prostate cancers, and could help predict whether these tumors will increase in size or spread to other parts of the body. In cancer cells, p300 mutations prevent the gene from producing any functional protein. Without p300, cells cannot effectively restrain growth and division, which can allow cancerous tumors to form.

Another intriguing connection of p300 is that it can be inhibited by the action of the sirtuin deacetylase Sirt1. (See here.)

P300/CBP themselves are targets of intense research activity. Their physical structure has only very recently been determined. (See here, here, here.)

Finally (for now), it's interesting that p300 plays a role in stem cell signaling through one of our favorite signaling pathways – Wnt (see here). According to this report: Stem Cell Signaling Mystery Solved, a small molecule called IQ-1 interferes with Wnt signaling via p300:
What IQ-1 does, Kahn explains, is to block one arm of a cell-signaling pathway called the Wnt pathway, while enhancing the signal coming from the other arm of the Wnt pathway. The Wnt pathway is known to have dichotomous effects on stem cells i.e. both proliferative and differentiative. More specifically, IQ-1 blocks the coactivator p300 from interacting with the protein ß-catenin; this prevents the stem cells from being 'told' to differentiate into a more specific cell type.

Additional reading:

A core Klf circuitry regulates self-renewal of embryonic stem cells – research abstract published online 2/10/08

Molecular Alliance Identified that Sustains Embryonic Stem-Cell State – another summary of the Klf4 study

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