The human leukemia oncogene bcr-abl abrogates the anchorage requirement but not the growth factor requirement for proliferation.
Proliferation of normal cells in a multicellular organism requires not only growth factors but also the proper attachment to the extracellular matrix. A hallmark of neoplastic transformation is the loss of anchorage dependence which usually accompanies the loss of growth factor requirement. The Bcr-Abl tyrosine kinase of human leukemias is shown here to abrogate only the anchorage, not the growth factor, requirement. Bcr-Abl-transformed cells grow in soft agar but do not proliferate in serum-free media. Bcr-Abl does not activate the mitogenic pathway, as indicated by its inability to induce enhancers such as the serum response element or the tetradecanoyl phorbol acetate response element (TRE). However, Bcr-Abl can alleviate the anchorage requirement for the induction of the TRE enhancer; i.e., it allows serum to activate the TRE in detached cells. This activity is dependent on the association of an active Bcr-Abl tyrosine kinase with the actin filaments. Despite its association with the adapter protein Grb2, Bcr-Abl's effect on the TRE enhancer is not blocked by dominant negative Ras or Raf. The finding that Bcr-Abl tyrosine kinase abrogates only anchorage dependence may have important implications on the pathogenesis of chronic myelogenous leukemia.
Renshaw
M W
MW
Department of Biology, University of California at San Diego, La Jolla 92093-0347.
McWhirter
J R
JR
Wang
J Y
JY
D016475:3T3 Cells; D000818:Animals; D002448:Cell Adhesion; D002455:Cell Division / Q000187:drug effects / Q000502:physiology*; D002460:Cell Line; D002471:Cell Transformation, Neoplastic; D002522:Chlorocebus aethiops; D004261:DNA Replication; D016044:Fusion Proteins, bcr-abl / Q000096:biosynthesis / Q000235:genetics*; D015870:Gene Expression; D016313:Genes, abl; D006133:Growth Substances / Q000494:pharmacology*; D006801:Humans; D007668:Kidney; D007938:Leukemia / Q000235:genetics*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics; D051379:Mice; D009857:Oncogenes; D011505:Protein-Tyrosine Kinases / Q000096:biosynthesis / Q000235:genetics*; D011994:Recombinant Proteins / Q000096:biosynthesis; D014162:Transfection
D006133:Growth Substances; D011994:Recombinant Proteins; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl