Of over 23,000 genes in the human genome, a very small role plays a very important role in signal transmission and growth regulation. Three of these genes encoding RAS proteins are particularly important because they mutate in more than 25% of human cancers. The processes surrounding the RAS gene are also responsible for a number of rare genetic developmental disorders in humans, RASopathien. RAS proteins are central, essential cell growth regulators and carcinogenesis, and any RAS regulator is the basis of cancer and other diseases.
On the basis of an interest in understanding the underlying genetic determinants of the drug's effect on the oncological disease of the hematopoietic system, CeMM together with MedUni Vienna now informs about the LZTR1 gene identification and its function. LZTR1 is associated with a number of rare diseases and cancer. Its importance is now identified in association with RAS proteins. These findings represent significant advances in the field of cell biology as they reveal previously unknown key controllers for a well-characterized and characterized cellular signaling pathway. In addition, the findings are far reaching because they not only illuminate the regulation of the central growth-promoting protein but also provide molecular explanation for the involvement of LZTR1 in many different diseases. These include, for example, various types of brain and childhood cancers, as well as developmental pathologies such as Noonan's syndrome.
The research team of Giulio Superti-Furga found that LZTR1 together with its partner cullin 3 puts a small molecular label called ubiquitin on RAS proteins. Ubiquitin-modified RAS proteins exhibited altered localization and abundance in the cell. Mutations or inactivation of LZTR1 led to an increase in RAS-dependent cellular signaling pathways and eventually to dysregulation of cell growth and differentiation. LZTR1 thus acts as a brake of RAS proteins and their activity in a cell.
Giulio Superti-Furga, head of study, scientific director of CeMM and Professor of Biology of Health Systems at the University of Medicine, Vienna, explains: "The study is part of a long-term effort to understand the mechanisms of cancer drugs used to treat leukemia and beyond. that I contributed to the discovery of a new fundamental aspect of RAS protein regulation as it is one of the most important cell growth regulators. "Johannes Bigenzahn, a postdoctoral colleague and lead author of the study, adds:" It is both medical and scientific looking very exciting to find the mechanism for so much various genetic diseases and many unusual forms of cancer. It is to be expected that our discovery in the future may lead to the development of new therapeutic strategies for RAS-dependent diseases. "
A scientific study was conducted in close collaboration with the research groups of the Marek Mlodzik group at the Mount Sinai Medical School in New York and Thijn Brummelkamp, the Netherlands Cancer Institute in Amsterdam and the PI aide at CeMM. A parallel study by the Anna Sablina research group and colleagues at the Belgian KU Leuven University confirms and extends the knowledge gained at CeMM and reaffirms the key role of LZTR1 in the regulation of cell growth and differentiation.
The publication: "LZTR1 is the Regulator of Ubiquitous and RAS Signaling" was published on November 15, 2018 in Science. DOI: 10,1126 / science.aap8210.
Authors: Johannes W. Bigenzahn, Giovanna M. Coll, Felix Kartnig, Melanie Pieraks, Gregory I. Vladimir, Leonhard X. Heinz, Vitaly Sedlarov, Fiorella Schischlik, Astrid Fauster, Manuele Rebsamen, Katja Parapatics, Vincent A. Blomen, André C Müller, Georg E. Winter, Robert Kralovic, Thijn R. Brummelkamp, Marek Mlodzik, Giulio Superti-Furga
Funding: This study was funded by the European Research Council (ERC), the Austrian Science Fund (FWF) and the Austrian Academy of Sciences (ÖAW).
Johannes Bigenzahn, [email protected]
"LZTR1 is the controller of the Ubiquitous and RAS Signaling" was published on November 15, 2018 in Science. DOI: 10,1126 / science.aap8210.