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Abstract
We have expressed several variants of core binding factor beta (CBFbeta)-smooth muscle myosin heavy chain (SMMHC) from the metallothionein promoter in Ba/F3 cells. Deletion of amino acids 2-11 from the CBFbeta segment, required for interaction with CBFalpha, prevented CBFbeta-SMMHC from inhibiting CBF DNA binding and cell cycle progression. Deletion of 283 carboxyl-terminal residues from the SMMHC domain, required for multimerization, also inactivated CBFbeta-SMMHC. Nuclear expression of CBFbeta(Delta2-11)-SMMHC was decreased relative to CBFbeta-SMMHC. CBFbeta(Delta2-11)-SMMHC linked to a nuclear localization signal still did not slow cell growth. The ability of each CBFbeta-SMMHC variant to inhibit CBF DNA binding and cell proliferation correlated with its ability to inhibit transactivation by an AML1-VP16 fusion protein. Thus, CBFbeta-SMMHC slows cell cycle progression from G1 to S phase by inhibiting CBF DNA binding and transactivation.
Highlights
The Core Binding Factor (CBF) ␣ Interaction Domain and the Smooth Muscle Myosin Heavy Chain (SMMHC) Segment of CBF-SMMHC Are Both Required to Slow Cell Proliferation*
We found that a CBF-SMMHC variant lacking amino acids 2–11 of the CBF segment did not interfere with CBF DNA binding or slow cell proliferation, whereas a variant lacking CBF amino acids 142–165 did
By expressing INV from the MT promoter in Ba/F3 and 32D cl3 cells, we provide evidence suggesting that lack of hematopoiesis in INV-expressing mice is due to inhibition of cell proliferation during G1 phase [14]
Summary
31534 –31540, 1998 Printed in U.S.A. The Core Binding Factor (CBF) ␣ Interaction Domain and the Smooth Muscle Myosin Heavy Chain (SMMHC) Segment of CBF-SMMHC Are Both Required to Slow Cell Proliferation*. Deletion of amino acids 2–11 from the CBF segment, required for interaction with CBF␣, prevented CBF-SMMHC from inhibiting CBF DNA binding and cell cycle progression. The ability of each CBF-SMMHC variant to inhibit CBF DNA binding and cell proliferation correlated with its ability to inhibit transactivation by an AML1-VP16 fusion protein. CBF-SMMHC slows cell cycle progression from G1 to S phase by inhibiting CBF DNA binding and transactivation. 25% of pediatric B-lineage acute lymphocytic leukemias contain t(12;21), which encodes TEL-AML1 [12, 13] Each of these “CBF oncoproteins” inhibits CBF activities (14 –20).
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