Inhibition of Nuclear Entry of MAPK Cascade Proteins as a Novel Mechanism for Treating Cancer (No. 1446)
Lead Researcher: Prof. Rony Seger
Peptide sequences for efficient inhibition of nuclear translocation of proteins.
The ability to regulate cellular localization of a biological component is important for many functions such as gene therapy, protection from toxic chemicals, transport of anti-cancer agents, and possibly preventing nuclear translocation of oncogenes. To ensure accurate cellular functioning, the spatial distribution of proteins needs to be delicately regulated and coordinated. This is particularly apparent in many signaling proteins that dynamically and rapidly change their localization upon extracellular stimulation. The present invention provides peptides that may be used to regulate the nuclear translocation of proteins that endogenously comprise such nuclear translocation signals.
Inhibition of translocation of endogenous oncogenes and thereby the transcription they induce.
Regulation of the level of nuclear targeting activity by selection of different amino acids in the peptide sequences.
Peptides can be modified in order to make them more stable in the body.
Modulation of the nuclear activities of proteins without harming their cytoplasmic activities.
The current invention identifies a 3-amino acid domain (Ser-Pro-Ser, SPS), which is a nuclear translocation signal present in signaling proteins such as extracellular signal-regulated kinase (ERK2) protein, SMAD3 and mitogen-activated protein kinase 1 (MEK1). SPS participates in nuclear translocation upon extracellular stimulation. Since several of these proteins are involved in the regulation of cellular proliferation and oncogenic transformation, the SPS domain can compete with the translocation machinery and therefore prevent the translocation of the proteins into the nucleus. As was shown in animal models, inhibiting this mechanism has an advantage over other ways of inhibition as it doesn’t lead to a negative feedback loop which may enhance the production of the protein.