Expression of the transcriptional repressor Gfi-1 is regulated by C/EBP  and is involved in its proliferation and colony formation-inhibitory effects in p210BCR/ABL-expressing cells

Lidonnici, M.R. et al. (2010) Expression of the transcriptional repressor Gfi-1 is regulated by C/EBP  and is involved in its proliferation and colony formation-inhibitory effects in p210BCR/ABL-expressing cells. Cancer Research, 70(20), pp. 7949-7959. (doi: 10.1158/0008-5472.CAN-10-1667)

Abstract

Ectopic expression of CAAT/enhancer binding protein a (C/EBP alpha) in p210BCR/ABL-expressing cells induces granulocytic differentiation, inhibits proliferation, and suppresses leukemogenesis. To dissect the molecular mechanisms underlying these biological effects, C/EBPa-regulated genes were identified by microarray analysis in 32D-p210BCR/ABL cells. One of the genes whose expression was activated by C/EBPa in a DNA binding-dependent manner in BCR/ABL-expressing cells is the transcriptional repressor Gfi-1. We show here that C/EBPa interacts with a functional C/EBP binding site in the Gfi-1 5'-flanking region and enhances the promoter activity of Gfi-1. Moreover, in K562 cells, RNA interference-mediated downregulation of Gfi-1 expression partially rescued the proliferation-inhibitory but not the differentiation-inducing effect of C/EBP alpha. Ectopic expression of wild-type Gfi-1, but not of a transcriptional repressor mutant (Gfi-1P2A), inhibited proliferation and markedly suppressed colony formation but did not induce granulocytic differentiation of BCR/ABL-expressing cells. By contrast, Gfi-1 short hairpin RNA-tranduced CD34(+) chronic myeloid leukemia cells were markedly more clonogenic than the scramble-transduced counterpart. Together, these studies indicate that Gfi-1 is a direct target of C/EBPa required for its proliferation and survival-inhibitory effects in BCR/ABL-expressing cells.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Holyoake, Professor Tessa
• Authors: Lidonnici, M.R., Audia, A., Soliera, A.R., Prisco, M., Ferrari-Amorotti, G., Waldron, T., Donato, N., Zhang, Y., Martinez, R.V., Holyoake, T.L., and Calabretta, B.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Cancer Research
• ISSN: 0008-5472