Wednesday, June 27, 2012

Wnt and TERT Signaling

Signaling pathways in the cells have been a major focus on study for the past decade or so. The focus generally has been on what protein or gene influences what other protein or gene. A recent article in Science presents some interesting work on Wnt and TERT.
Wnt is an extra cellular signaling protein and it attaches to Frizlled a receptor and sets off a cascade that moves B catenin into the nucleus and generates Myc which is a transcription protein with together with catenin and other transcription proteins generates Tert from TERT.

To quote from NCBI:

Telomerase is a ribonucleoprotein polymerase that maintains telomere ends by addition of the telomere repeat TTAGGG. The enzyme consists of a protein component with reverse transcriptase activity, encoded by this gene, and an RNA component which serves as a template for the telomere repeat. Telomerase expression plays a role in cellular senescence, as it is normally repressed in postnatal somatic cells resulting in progressive shortening of telomeres. Deregulation of telomerase expression in somatic cells may be involved in oncogenesis.  

As the Science article states:

Maintaining the length of telomere, the ends of chromosomes, is essential for all cells that divide many times. The enzyme telomerase lengthens these ends, counterbalancing their shortening that occurs each time chromosomes are copied. Telomerase is essential for cell viability, and loss of its function from the loss of only one of two copies of the encoding gene can lead to the failure of stem cell renewal that is seen in premature aging conditions such as dyskeratosis congenita, aplastic  anemia, and pulmonary fibrosis. Conversely, telomerase activity is increased in many cancers  and may be required for cancer cells to maintain their telomere length...

 They continue is a rather interesting wording:

Because of the importance of telomerase expression, the signaling pathways that control TERT transcription have been extensively studied. Remarkably, many different transcription factors, including c-Myc, Sp1, nuclear factor of activated T cells (NFAT), activating protein 2B, nuclear  factor κB (NF-κB), Myb, activating transcription factor, nuclear factor 1 (NF1), and the estrogen receptor (ER), bind to the 330–base pair minimal TERT promoter and regulate transcription. In addition, a number of negative regulators bind the TERT promoter, including CTCF, elongation factor 2, p53, Ets, Mad1, Men1, and Wt1. Adding β-catenin and Klf4 to the many regulators that bind the TERT promoter is like adding one more guest to a crowded table at a dinner party.

They conclude:

It is reasonable to propose that Wnt regulates TERT given that Wnt signaling plays an essential role in stem cell self-renewal and that TERT is needed for the long-term growth of stem cells. TERT  regulation seems to require not one, but two master transcriptional regulators to assure that there is  neither too much, which may allow the growth of cancer cells, nor too little, which might lead to stem cell failure. The fi nding by Hoffmeyer et al. that both β-catenin and Klf4 are required to activate  TERT expression puts the horse (Wnt) before the cart (TERT) and provides a foundation for linking  telomerase levels and self-renewal.

The observation of the inter-cellular signalling with Wnt and its control over TERT and the telomere process is quite interesting. This may be an interesting way to incorporate many of the Turing models we have been discussing as well.