Inhibitors of the T cell-specific alternative p38 activation pathway and methods of use

摘要

In T lymphocytes, p38 mitogen activated protein kinase (MAPK) can be activated through an alternative pathway that involves phosphorylation at tyrosine 323. Disclosed herein is the identification of a minimal region of the growth arrest and DNA damage-inducible alpha (Gadd45α) protein that is required for binding to and inhibition of tyrosine 323-phosphorylated p38 in T cells. The disclosed Gadd45α polypeptides inhibit proliferation of T cells in response to T cell receptor stimulation, inhibit differentiation of T cells into Th1 or Th17 cells, inhibit the production of proinflammatory cytokines, and reduce tumor formation and growth of inflammatory cancers, such as pancreatic cancer.

主权项

1. An isolated growth arrest and DNA-damage-inducible alpha (Gadd45α) polypeptide no more than 25 amino acids in length, wherein the amino acid sequence of the polypeptide comprises LQIHFTLIXAFCCEN (SEQ ID NO: 1), wherein X is Q or R.