Graded inhibition of oncogenic Ras-signaling by multivalent Ras-binding domains

Cell Communication and Signaling

Research

Ignacio Rubio¹  Karlheinz Friedrich²  Martin Augsten³  Anika Böttcher⁴  Rainer Spanbroek⁵ 

[1] Center for Sepsis Control and Care, University Hospital Jena, Jena, Germany;Institute of Molecular Cell Biology, University Hospital Jena, Jena, Germany;Institute of Biochemistry II, University Hospital Jena, Jena, Germany;Institute of Biochemistry II, University Hospital Jena, Jena, Germany;Department of Oncology-Pathology, Karolinska Institutet, 171 76, Stockholm, Sweden;Institute of Biochemistry II, University Hospital Jena, Jena, Germany;German Research Center for Environmental Health, Neuherberg, Germany;Institute of Vascular Medicine, University Hospital Jena, Jena, Germany;

关键词: Cellular transformation;    Ras;    RBD;    Tet-off system;    m;   

DOI  :  10.1186/1478-811X-12-1

 received in 2013-10-01, accepted in 2013-12-26,  发布年份 2014

来源: Springer

【 摘 要 】

BackgroundRas is a membrane-associated small G-protein that funnels growth and differentiation signals into downstream signal transduction pathways by cycling between an inactive, GDP-bound and an active, GTP-bound state. Aberrant Ras activity as a result of oncogenic mutations causes de novo cell transformation and promotes tumor growth and progression.ResultsHere, we describe a novel strategy to block deregulated Ras activity by means of oligomerized cognate protein modules derived from the Ras-binding domain of c-Raf (RBD), which we named MSOR for m ultivalent s cavengers of o ncogenic R as. The introduction of well-characterized mutations into RBD was used to adjust the affinity and hence the blocking potency of MSOR towards activated Ras. MSOR inhibited several oncogenic Ras-stimulated processes including downstream activation of Erk1/2, induction of matrix-degrading enzymes, cell motility and invasiveness in a graded fashion depending on the oligomerization grade and the nature of the individual RBD-modules. The amenability to accurate experimental regulation was further improved by engineering an inducible MSOR-expression system to render the reversal of oncogenic Ras effects controllable.ConclusionMSOR represent a new tool for the experimental and possibly therapeutic selective blockade of oncogenic Ras signals.

【 授权许可】

CC BY   
© Augsten et al.; licensee BioMed Central Ltd. 2014