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  • Title: Cell-penetrating SH3 domain blocker peptides inhibit proliferation of primary blast cells from CML patients.
    Author: Kardinal C, Konkol B, Schulz A, Posern G, Lin H, Adermann K, Eulitz M, Estrov Z, Talpaz M, Arlinghaus RB, Feller SM.
    Journal: FASEB J; 2000 Aug; 14(11):1529-38. PubMed ID: 10928987.
    Abstract:
    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.
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