Česká Genetická Banka

NATURE: 3. - 10. 1. 2013

NATURE: Restriction of intestinal stem cell expansion and the regenerative response by YAP

"A remarkable feature of regenerative processes is their ability to halt proliferation once an organ’s structure has been restored. The Wnt signalling pathway is the major driving force for homeostatic self-renewal and regeneration in the mammalian intestine. However, the mechanisms that counterbalance Wnt-driven proliferation are poorly understood. Here we demonstrate in mice and humans that yes-associated protein 1 (YAP; also known as YAP1)—a protein known for its powerful growth-inducing and oncogenic properties—has an unexpected growth-suppressive function, restricting Wnt signals during intestinal regeneration. Transgenic expression of YAP reduces Wnt target gene expression and results in the rapid loss of intestinal crypts. In addition, loss of YAP results in Wnt hypersensitivity during regeneration, leading to hyperplasia, expansion of intestinal stem cells and niche cells, and formation of ectopic crypts and microadenomas. We find that cytoplasmic YAP restricts elevated Wnt signalling independently of the AXIN–APC–GSK-3β complex partly by limiting the activity of dishevelled (DVL). DVL signals in the nucleus of intestinal stem cells, and its forced expression leads to enhanced Wnt signalling in crypts. YAP dampens Wnt signals by restricting DVL nuclear translocation during regenerative growth. Finally, we provide evidence that YAP is silenced in a subset of highly aggressive and undifferentiated human colorectal carcinomas, and that its expression can restrict the growth of colorectal carcinoma xenografts. Collectively, our work describes a novel mechanistic paradigm for how proliferative signals are counterbalanced in regenerating tissues. Additionally, our findings have important implications for the targeting of YAP in human malignancies.

http://www.nature.com/nature/journal/v493/n7430/full/nature11693.html

 

NATURE: Structural biology: Membrane enzyme cuts a fine figure

"Malfunction of presenilin enzymes, which cleave proteins in cell membranes, can lead to Alzheimer's disease. A crystal structure of a microbial presenilin provides insights into the workings of this enzyme family."

http://www.nature.com/nature/journal/v493/n7430/full/nature11768.html

 

SCIENCE: Cell Biology: The Immune System's Compact Genomic Counterpart

"Much of the human genome derives from self-serving DNA strands known as transposons. These genetic gypsies often jump to new chromosome locations, sometimes disabling genes and even triggering cancer. For that reason, a specialized group of RNA molecules known as piRNAs are the superheroes of animal genomes. piRNAs team up with certain proteins to shackle transposons in animal germline cells, creating a molecular defense that scientists liken to an immune system for the genome."

http://www.sciencemag.org/content/339/6115/25.summary