The BCR-ABL tyrosine kinase inhibits apoptosis by activating a Ras-dependent signaling pathway.
BCR-ABL is a deregulated tyrosine kinase that is expressed in Philadelphia chromosome (Ph1) positive human leukemias. When expressed in hematopoietic cells, BCR-ABL causes cytokine independent proliferation, induces tumorigenic growth and prevents apoptosis in response to cytokine deprivation or DNA damage. One mechanism by which BCR-ABL signals in cells is by activating the small guanine nucleotide binding protein Ras. BCR-ABL-transformed cells have constitutively high levels of active, GTP-bound Ras. Here we use 32D cells that inducibly express a dominant negative Ras protein to define the Ras requirements in BCR-ABL-transformed cells. Dominant negative Ras inhibits BCR-ABL-mediated Ras activation, and induces cell death by an apoptotic mechanism. Therefore, BCR-ABL inhibits apoptosis through activation of a Ras-dependent signaling pathway.
Cortez
D
D
Department of Molecular Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710, USA.
Stoica
G
G
Pierce
J H
JH
Pendergast
A M
AM
D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002461:Cell Line, Transformed / Q000187:drug effects; D003907:Dexamethasone / Q000494:pharmacology; D016044:Fusion Proteins, bcr-abl / Q000235:genetics / Q000502:physiology*; D006801:Humans; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*
D018931:Antineoplastic Agents, Hormonal; D003907:Dexamethasone; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl; D018631:ras Proteins