Abstract
Oncogenic forms of the Abl and Src tyrosine kinases trigger the destruction of the Abi proteins, a family of Abl-interacting proteins that antagonize the oncogenic potential of Abl after overexpression in fibroblasts. The destruction of the Abi proteins requires tyrosine kinase activity and is dependent on the ubiquitin-proteasome pathway. We show that degradation of the Abi proteins occurs through a Ras-independent pathway. Significantly, expression of the Abi proteins is lost in cell lines and bone marrow cells isolated from patients with aggressive Bcr-Abl-positive leukemias. These findings suggest that loss of Abi proteins may be a component in the progression of Bcr-Abl-positive leukemias and identify a novel pathway linking activated nonreceptor protein tyrosine kinases to the destruction of specific target proteins through the ubiquitin-proteasome pathway.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adaptor Proteins, Signal Transducing*
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Animals
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Bone Marrow / metabolism
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Bone Marrow / pathology
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Cysteine Endopeptidases / metabolism
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Cytoskeletal Proteins*
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Fusion Proteins, bcr-abl / physiology*
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Gene Expression Regulation, Leukemic*
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Homeodomain Proteins / genetics
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Homeodomain Proteins / metabolism*
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Humans
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Leukemia / genetics*
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Leukemia / metabolism
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Leukemia / pathology
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive / genetics
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive / metabolism
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive / pathology
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Mice
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Multienzyme Complexes / metabolism
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Neoplasm Proteins / genetics
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Neoplasm Proteins / physiology*
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Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / genetics
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Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / metabolism
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Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / pathology
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Proteasome Endopeptidase Complex
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Protein Processing, Post-Translational*
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Proto-Oncogene Proteins c-abl / physiology*
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Proto-Oncogene Proteins pp60(c-src) / physiology*
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Tumor Cells, Cultured
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Ubiquitins / physiology*
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ras Proteins / physiology*
Substances
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ABI1 protein, human
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ABI2 protein, human
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Abi1 protein, mouse
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Abi2 protein, mouse
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Adaptor Proteins, Signal Transducing
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Cytoskeletal Proteins
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Homeodomain Proteins
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Multienzyme Complexes
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Neoplasm Proteins
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Ubiquitins
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Fusion Proteins, bcr-abl
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Proto-Oncogene Proteins c-abl
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Proto-Oncogene Proteins pp60(c-src)
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Cysteine Endopeptidases
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Proteasome Endopeptidase Complex
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ras Proteins