Xm. Zou et al., INDUCTION OF C-MYC TRANSCRIPTION BY THE V-ABL TYROSINE KINASE REQUIRES RAS, RAF1, AND CYCLIN-DEPENDENT KINASES, Genes & development, 11(5), 1997, pp. 654-662
v-Abl is an oncogenic form of the c-Abl nonreceptor tyrosine kinase. v
-Abl induces transcription of c-myc, and c-Myc function is a necessary
but not sufficient component of the v-Abl transformation program. Pre
viously we showed that the E2F site in the c-myc promoter is a v-Abl r
esponse element and that v-Abl appears to induce c-myc by initiating a
phosphorylation cascade that ultimately activates E2F-binding protein
s. In this work we have investigated the signaling pathway between the
v-Abl tyrosine kinase and activated E2F proteins. We show that the Pa
s GTPase and Raf1 serine/threonine kinase are required in this pathway
. However, in contrast to other aspects of v-Abl signaling, induction
of c-myc transcription is independent of the Rac GTPase. Our results a
lso establish a requirement for activated cyclin-dependent kinases (cd
ks), as v-Abl-dependent induction of c-myc transcription is blocked by
cdk inhibitor p21 and induction of c-myc is accompanied by activation
of cdk2 and cdk4. Finally, we show that v-Abl-dependent induction of
c-myc is accompanied by hyperphosphorylation of pRb, p107, and p130. O
n the basis of these data, we propose a model for the signaling path f
rom v-Abl to c-myc.