Functional role of CCCTC binding factor in insulin‐stimulated cell proliferation

Abstract

CCCTC binding factor (CTCF) is a nuclear protein containing an 11-zinc-finger DNA-binding domain. CTCF plays important roles in the regulation of epigenetics and gene transcription. As a multifunctional protein, CTCF is also involved in the regulation of cell proliferation and of apoptosis. However, mechanisms underlining the regulatory function of CTCF in mediating growth factor- and cytokine-stimulated cell fate are largely unknown. The effect of CTCF on insulin-induced ML-1 cell proliferation was investigated by studying insulin-stimulated extracellular signal-regulated kinase (Erk) and Akt signalling pathways, and the alterations of CTCF activity in these cells. The present study demonstrates that insulin-induced human haematopoietic myeloblastic ML-1 cell proliferation requires increased CTCF expression. Inhibition of Erk and Akt pathways with specific blockers or by dominantly negative expression of Erk and Akt mutants markedly suppressed expression of CTCF and resulted in retardation of cell proliferation. Furthermore, insulin-induced ML-1 cell proliferation was significantly enhanced by overexpression of cDNA encoding full-length CTCF. In contrast, ML-1 cell proliferation was inhibited by knocking down CTCF mRNA using specific small interference RNA. Our results indicate that CTCF is indeed a protein with multifunctional activity that plays a significant role in modulating signalling pathways to mediate insulin-induced ML-1 cell proliferation.