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Targeting the non‐ATP‐binding pocket of the MAP kinase p38γ mediates a novel mechanism of cytotoxicity in cutaneous T‐cell lymphoma (CTCL)
Author(s) -
Zhang Xu Hannah,
Chen ChihHong,
Li Hongzhi,
Hsiang Jack,
Wu Xiwei,
Hu Weidong,
Horne David,
Nam Sangkil,
Shively Jack,
Rosen Steven T.
Publication year - 2021
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1002/1873-3468.14186
Subject(s) - cutaneous t cell lymphoma , peripheral blood mononuclear cell , cytotoxicity , p38 mitogen activated protein kinases , kinase , cytotoxic t cell , lymphoma , cancer research , protein kinase a , biology , microbiology and biotechnology , chemistry , computational biology , biochemistry , immunology , mycosis fungoides , in vitro
We describe here for the first time a lipid‐binding‐domain (LBD) in p38γ mitogen‐activated protein kinase (MAPK) involved in the response of T cells to a newly identified inhibitor, CSH71. We describe how CSH71, which binds to both the LBD and the ATP‐binding pocket of p38γ, is selectively cytotoxic to CTCL Hut78 cells but spares normal healthy peripheral blood mononuclear (PBMC) cells, and propose possible molecular mechanisms for its action. p38γ is a key player in CTCL development, and we expect that the ability to regulate its expression by specifically targeting the lipid‐binding domain will have important clinical relevance. Our findings characterize novel mechanisms of gene regulation in T lymphoma cells and validate the use of computational screening techniques to identify inhibitors for therapeutic development.