Tyrosine kinase oncogenes abrogate interleukin-3 dependence of murine myeloid cells through signaling pathways involving c-myc: conditional regulation of c-myc transcription by temperature-sensitive v-abl.
Retroviral expression vectors carrying the tyrosine kinase oncogenes abl, fms, src, and trk abrogate the requirements of murine myeloid FDC-P1 cells for interleukin-3 (IL-3). Factor-independent clones constitutively express c-myc in the absence of IL-3, whereas in parental cultures c-myc transcription requires the presence of the ligand. To directly test the effect of a tyrosine kinase oncogene on c-myc expression, retroviral constructs containing three different temperature-sensitive mutants of v-abl were introduced into myeloid IL-3-dependent FDC-P1 and 32D cells. At the permissive temperature, clones expressing temperature-sensitive abl behaved like wild-type abl-containing cells in their growth properties and expressed c-myc constitutively. Temperature shift experiments demonstrated that both IL-3 abrogation and the regulation of c-myc expression correlated with the presence of functional v-abl. Induction of c-myc expression by reactivation of temperature-sensitive v-abl mimicked c-myc induction by IL-3 in that it did not require protein synthesis and occurred at the level of transcription, with effects on both initiation and a transcription elongation block. However, v-abl-regulated FDC-P1 cell growth differed from IL-3-regulated growth in that c-fos and junB, which are normally induced by IL-3, were not induced by activation of v-abl.
Cleveland
J L
JL
Laboratory of Viral Carcinogenesis, National Cancer Institute, Frederick, Maryland 21701.
Dean
M
M
Rosenberg
N
N
Wang
J Y
JY
Rapp
U R
UR
D000818:Animals; D002460:Cell Line; D002999:Clone Cells; D015972:Gene Expression Regulation, Neoplastic; D007377:Interleukin-3 / Q000494:pharmacology*; D009052:Leukemia Virus, Murine / Q000235:genetics*; D008979:Moloney murine leukemia virus / Q000235:genetics; D009857:Oncogenes / Q000187:drug effects; D011401:Promoter Regions, Genetic; D011505:Protein-Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D016271:Proto-Oncogene Proteins c-myc; D011519:Proto-Oncogenes / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D013696:Temperature; D014158:Transcription, Genetic
D007377:Interleukin-3; D011518:Proto-Oncogene Proteins; D016271:Proto-Oncogene Proteins c-myc; D011505:Protein-Tyrosine Kinases