OVEREXPRESSION OF CORE-BINDING FACTOR-ALPHA (CBF-ALPHA) REVERSES CELLULAR-TRANSFORMATION BY THE CBF-BETA-SMOOTH MUSCLE MYOSIN HEAVY-CHAIN CHIMERIC ONCOPROTEIN
A. Hajra et al., OVEREXPRESSION OF CORE-BINDING FACTOR-ALPHA (CBF-ALPHA) REVERSES CELLULAR-TRANSFORMATION BY THE CBF-BETA-SMOOTH MUSCLE MYOSIN HEAVY-CHAIN CHIMERIC ONCOPROTEIN, Molecular and cellular biology, 15(9), 1995, pp. 4980-4989
A fusion between the transcription factor core-binding factor beta (CB
F beta; also known as PEBP2 beta) and the tail region of smooth muscle
myosin heavy chain (SMMHC) is generated by an inversion of chromosome
16 [inv(16) (p13q22)] associated with the M4Eo subtype of acute myelo
id leukemia. We have previously shown that this CBF beta-SMMHC chimeri
c protein can transform NIH 3T3 cells and that this process requires r
egions of the chimeric protein necessary for association with the CBF
alpha subunit. In this study, we show that NIH 3T3 cells overexpressin
g murine Cbf alpha 2 (also known as Aml1) cannot be transformed by CBF
beta-SMMHC and that overexpression of Cbf alpha 2 in cells previously
transformed by CBF beta-SMMHC reverts the cells to a less transformed
phenotype. Cbf alpha 2 overexpression does not cause any gross morpho
logical changes to NIH 3T3 cells but does result in increased CBF acti
vity, as indicated by electrophoretic mobility shift assays and transa
ctivation of reporter constructs. Cells transformed by CBF beta-SMMHC
lack normal CBF-DNA complexes and have decreased levels of transactiva
tion. Reversion of CBF beta-SMMHC transformation by Cbf alpha 2 is ass
ociated with a restoration of normal CBF-DNA complexes and transactiva
tion activity. A Cbf alpha 2 mutant lacking transactivation properties
does not transform cells when overexpressed, nor does it protect cell
s from CBF beta-SMMHC transformation. These results suggest that CBF b
eta-SMMHC interferes with the normal function of CBF and that this int
erference is necessary but not sufficient for cellular transformation.