Abstract
The transforming abl proteins p160gag-abl, p185bcr-abl, and p210bcr-abl and the normal protein p140c-abl have identical catalytic sites, but differ in their N-terminal domains. Previous studies have indicated that the transforming abl proteins possess higher tyrosine kinase activity than the normal abl proto-oncogene product. In the present study, we demonstrate that two transforming abl proteins, p210bcr-abl and p160gag-abl, exhibit a higher affinity toward ATP and synthetic tyrosine containing substrates than p140c-abl. Furthermore, protein tyrosine kinase blockers from the tyrphostin family can discriminate between normal abl and transforming abl proteins of both human and mouse origin. These results suggest that the transforming potency of the abl proteins may result from their higher affinities toward intracellular signal transducers and demonstrate for the first time that oncogene products can differ from their homologous proto-oncogene product in substrate specificity. The ability of tyrphostins to discriminate between normal and transforming abl proteins suggests that it may be possible to design specific abl kinase inhibitors to combat abl-associated human leukemias.
Highlights
The transformingab1 proteins p160g"g~apb1',85bc""b', from a t(9:22) translocation, joining the proto-oncogene ab1 and p210bc"ab' andthe normal protein ~140"+'~' have from chromosome 9 with thebcr gene on chromosome 22 (4identical catalytic sites, but differ in their N-terminal 7)
It hasalso been suggested that the intrinsic protein tyrosine kinase activity of the transforming ab1 proteins ishigher than thatof the normal~ 1 4 0 " "(~2')
I t was initially identified as thetransformingcomponent of the Abelson murine leukemia virus, a murineretrovirusthat causesnonthymiclymphomain mice [3]
Summary
The transformingab1 proteins p160g"g~apb1',85bc""b', from a t(9:22) translocation, joining the proto-oncogene ab1 and p210bc"ab' andthe normal protein ~140"+'~' have from chromosome 9 with thebcr gene on chromosome 22 (4identical catalytic sites, but differ in their N-terminal 7). The ability of tyrphostins to discriminate between normal and transforming ab1 proteins suggests that it may be possible to design specific ab1 kinase inhibitors to combat ablassociated human leukemias. Lug0 et al [20] demonstrated a correlation between the tyrosine kinase activities of human bcr-ab1 proteins and cell transformation.
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