Cell Cycle and Transcriptional Control of Human Myeloid Leukemic Cells by Transforming Growth Factor Beta

Abstract

TGFβ1 is a potent growth inhibitor of both primitive and more differentiated human myeloid leukemic cells. The extent of the growth inhibitory response to TGFP varies with cell type, and is not linked to stages of differentiation of cell lines. Downregulation of multiple cell cycle-regulatory molecules is a dominant event in TGFβ1-mediated growth inhibition of human MV4-11 myeloid leukemia cells. Both G1-phase and G2-phase cyclins and cdks participate in the regulation of TGFβ1-mediated growth inhibition of MV4-11 cells. By both depressing cdk2 synthesis and up-regulating cyclin E-associated p27, TGFβ1 may magnify its inhibitory efficiency. TGFβ1 also rapidly inhibits phosphorylation of pRb at several serine and threonine residues. The underphosphorylated pRb associates with E2F-4 in G1 phase, whereas the phosphorylated pRb mainly binds to E2F-1 and E2F-3 in proliferating MV4-11 cells. Since TGFpi upregulates p130/E2F-4 complex formation and downregulates p107/E2F-4 complex formation, with E2F-4 levels remaining constant, our results suggest that E2F-4 is switched from pl07 to pRb and p130 when cells exit from the cell cycle and arrest in G1 by TGFpi. In summary, TGFpi inhibits growth of human myeloid leukemic cells through multiple pathways, whereas the “cdk inhibitor” p27 is both a positive and negative regulator.

Key Words:

• Transforming growth factor
• myeloid leukemia
• Cell Line
• Cell Cycle
• Rb protein
• Cyclin
• Cdk
• E2F