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Cell‐penetrating SH3 domain blocker peptides inhibit proliferation of primary blast cells from CML patients
Author(s) -
Kardinal Christian,
Konkol Birgit,
Schulz Axel,
Posern Guido,
Lin Hui,
Adermann Knut,
Eulitz Manfred,
Estrov Zeev,
Talpaz Moshe,
Arlinghaus Ralph B.,
Feller Stephan M.
Publication year - 2000
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.99-0850com
Subject(s) - breakpoint cluster region , chemistry , tyrosine kinase , cancer research , cell growth , k562 cells , sh3 domain , abl , microbiology and biotechnology , signal transducing adaptor protein , mapk/erk pathway , kinase , cell , biology , signal transduction , receptor , biochemistry
Bcr‐Abl contributes prominently to the development of most chronic myeloid leukemias (CMLs). Prior work has identified the adapter protein CRKL as a major substrate of the Bcr‐Abl tyrosine kinase. CRKL can also bind via its first SH3 domain [SH3(1)] to specific sequences in Bcr‐Abl. Cell‐penetrating peptides were developed that bind with high affinity and selectivity to the SH3(1) domain of CRKL. They disrupt Bcr‐Abl‐CRKL complexes and strongly reduce the proliferation of primary CML blast cells and cell lines established from Bcr‐Abl‐positive patients. Activation‐specific antibodies against phosphorylated MAP kinase (MAPK) showed that MAPK activity is down‐regulated in blast cells treated with the CRKLSH3(1) blocker peptides. We conclude that the Bcr‐Abl‐CRKL complexes are largely dependent on the CRKLSH3(1) domain, that the central mitogenic cascade is down‐regulated as a consequence of the disruption of CRKLSH3(1) interactions, and that CRKL therefore contributes to the proliferation of CML blast cells.–Kardinal, C., Konkol, B., Schulz, A., Posern, G., Lin, H., Adermann, K., Eulitz, M., Estrov, Z., Talpaz, M., Arlinghaus, R. B., Feller, S. M. Cell‐penetrating SH3 domain blocker peptides inhibit proliferation of primary blast cells from CML patients. FASEB J. 14, 1529–1538 (2000)