Cell cycle arrest by tyrosine kinase Abl involves altered early mitogenic response.
Activated forms of the nuclear and cytoplasmic tyrosine kinase c-Abl are completely cytoplasmic and oncogenic. The overexpression of c-Abl, and in certain fibroblast cell lines even of v-Abl, leads to a cell cycle arrest revealing an alternative Abl function. To facilitate the analysis of this growth inhibitory function we have taken advantage of regulable Abl-estrogen receptor (ABL:ER) fusion proteins. Oncogenic in the presence of estrogen, they are reversibly switched to inhibit cell proliferation upon removal of hormone. Using this system, we demonstrate that inhibition is effected by Abl derivatives which we have previously shown to be hypo-phosphorylated and to have low kinase activity. Since an almost exclusively cytoplasmic ABL:ER protein is fully growth inhibitory, relevant interactions may occur in the cytoplasm. We identify the cell cycle arrest as an early G1 or G0-like block. Interestingly, growth inhibition correlates with an altered expression pattern of early serum response genes; c-Jun mRNA and c-Fos protein levels are elevated in Abl-blocked cells. In view of the two functional modes of overexpressed Abl proteins, one can speculate that normal c-Abl may be involved in relaying growth regulatory signals from the membrane to the nucleus.
Mattioni
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T
Département de Biologie Cellulaire, Université de Genève, Switzerland.
Jackson
P K
PK
Bchini-Hooft van Huijsduijnen
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O
Picard
D
D
D016475:3T3 Cells; D000818:Animals; D001483:Base Sequence; D002453:Cell Cycle; D003593:Cytoplasm / Q000378:metabolism; D017931:DNA Primers / Q000737:chemistry; D015870:Gene Expression; D016762:Genes, fos; D016758:Genes, jun; D016259:Genes, myc; D006131:Growth Inhibitors; D066298:In Vitro Techniques; D051379:Mice; D008938:Mitosis; D008969:Molecular Sequence Data; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D016315:Proto-Oncogene Proteins c-abl / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics
D017931:DNA Primers; D006131:Growth Inhibitors; D012333:RNA, Messenger; D011505:Protein-Tyrosine Kinases; D016315:Proto-Oncogene Proteins c-abl