Abstract
Transformation mediated by the v-Abl oncoprotein, a tyrosine kinase encoded by the Abelson murine leukemia virus, is a multi-step process requiring genetic alterations in addition to expression of v-Abl. Loss of p53 or p19ARF was previously shown to be required for Abelson murine leukemia virus transformation of primary mouse embryonic fibroblasts (MEFs). By comparing gene expression patterns in primary p53-/- MEFs acutely infected with the v-Abl retrovirus, v-Abl-transformed MEF clones, and v-Abl-transformed MEF clones treated with Abl kinase inhibitor STI 571, we have identified additional genetic alterations associated with v-Abl transformation. Bcl-xL mRNA was elevated in three of five v-Abl-transformed MEF clones. In addition, elevated expression of c-Myc mRNA, caused either by c-myc gene amplification or by enhanced signaling via STAT3, was observed in five v-Abl-transformed MEF clones. The data suggest that increases in cell survival associated with Bcl-xL and increases in cell growth associated with c-Myc facilitate the transformation process dependent on constitutive mitogenic signaling by v-Abl.
Highlights
Transformation mediated by the v-Abl oncoprotein, a tyrosine kinase encoded by the Abelson murine leukemia virus, is a multi-step process requiring genetic alterations in addition to expression of v-Abl
By comparing gene expression patterns in primary p53؊/؊ mouse embryonic fibroblasts (MEFs) acutely infected with the v-Abl retrovirus, v-Abl-transformed MEF clones, and v-Abl-transformed MEF clones treated with Abl kinase inhibitor STI 571, we have identified additional genetic alterations associated with vAbl transformation
The v-Abl oncoprotein is a nonreceptor tyrosine kinase encoded by the Abelson murine leukemia virus (A-MuLV),1 which causes pro-/pre-B cell lymphomas in mice [1, 2]. v-Abl provides an excellent system for dissecting the individual molecular events required for malignant transformation. v-Abl constitutively activates multiple signaling pathways, including the Ras, Rac, phosphatidylinositol 3-kinase, and STAT pathways, all of which contribute to its transforming potential [3, 4]
Summary
A-MuLV, Abelson murine leukemia virus; STAT, signal transducers and activators of transcription; MEF, mouse embryonic fibroblast; RPA, RNase protection assay; CHAPS, 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonic acid. Loss of p53 causes genetic instability (10 –12), which would be predicted to accelerate additional genetic alterations that might enhance v-Abl-dependent transformation. We exploited these characteristics of p53Ϫ/Ϫ MEFs to create an experimental system for identification of genetic changes associated with v-Abl-dependent transformation. Overexpression of c-Myc provided v-Abl-transformed MEF clones with a growth advantage, which was evident in their decreased doubling times and elevation of telomerase activity.
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