A retroviral library genetic screen identifies IRF-2 as an inhibitor of N-ras-induced growth suppression in leukemic cells.
Activating mutations of the N-ras gene occur at relatively high frequency in acute myeloid leukemia and myelodysplastic syndrome. Somewhat paradoxically, ectopic expression of activated N-ras in primary hematopoietic cells and myeloid cell lines (in some cases) can lead to inhibition of proliferation. Expression of mutant N-ras in murine hematopoietic stem/progenitor cells is sufficient to induce myeloid malignancies, but these pathologies occur with long latency. This suggests that mutations that disable the growth suppressive properties of N-ras in hematopoietic cells are required for the development of frank malignancy. In the present work, the growth suppression induced by a mutant N-ras gene in U937 myeloid cells was used as the basis to screen a retroviral cDNA library for genes that prevent mutant N-ras-induced growth suppression (i.e., putative cooperating oncogenes). This screen identified the gene for the transcription factor interferon regulatory factor-2 (IRF-2), and as confirmation of the screen, overexpression of this gene in U937 cells was shown to inhibit mutant N-ras-induced growth suppression. Also recovered from the screen were two truncated clones of an uncharacterized gene (interim official symbol: PP2135). Overexpression of this truncated PP2135 gene in U937 cells did not appear to abrogate mutant N-ras-induced growth suppression, but rather appeared to confer an increased sensitivity of U937 cells to retroviral infection, accounting for the recovery of this gene from the genetic screen.
Passioura
Toby
T
School of Medical Sciences, University of New South Wales, Kensington, Sydney, Australia.
Shen
Sylvie
S
Symonds
Geoff
G
Dolnikov
Alla
A
D015152:Blotting, Northern; D049109:Cell Proliferation; D015870:Gene Expression; D015723:Gene Library; D011905:Genes, ras / Q000502:physiology*; D006801:Humans; D050836:Interferon Regulatory Factor-2 / Q000502:physiology*; D009154:Mutation / Q000235:genetics*; D016133:Polymerase Chain Reaction; D012190:Retroviridae / Q000235:genetics*; D020298:U937 Cells / Q000166:cytology / Q000378:metabolism
C494229:IRF2 protein, human; D050836:Interferon Regulatory Factor-2