TY - JOUR
T1 - Expression of the transcriptional repressor Gfi-1 is regulated by C/EBPα and is involved in its proliferation and colony formation-inhibitory effects in p210BCR/ABL-expressing cells
AU - Lidonnici, Maria Rosa
AU - Audia, Alessandra
AU - Soliera, Angela Rachele
AU - Prisco, Marco
AU - Ferrari-Amorotti, Giovanna
AU - Waldron, Todd
AU - Donato, Nick
AU - Zhang, Ying
AU - Martinez, Robert V.
AU - Holyoake, Tessa L.
AU - Calabretta, Bruno
PY - 2010/10/15
Y1 - 2010/10/15
N2 - Ectopic expression of CAAT/enhancer binding protein α (C/EBPα) in p210BCR/ABL-expressing cells induces granulocytic differentiation, inhibits proliferation, and suppresses leukemogenesis. To dissect the molecular mechanisms underlying these biological effects, C/EBPα-regulated genes were identified by microarray analysis in 32D-p210BCR/ABL cells. One of the genes whose expression was activated by C/EBPα in a DNA binding - dependent manner in BCR/ABL-expressing cells is the transcriptional repressor Gfi-1. We show here that C/EBPα 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/EBPα. 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/EBPα required for its proliferation and survival-inhibitory effects in BCR/ABL-expressing cells.
AB - Ectopic expression of CAAT/enhancer binding protein α (C/EBPα) in p210BCR/ABL-expressing cells induces granulocytic differentiation, inhibits proliferation, and suppresses leukemogenesis. To dissect the molecular mechanisms underlying these biological effects, C/EBPα-regulated genes were identified by microarray analysis in 32D-p210BCR/ABL cells. One of the genes whose expression was activated by C/EBPα in a DNA binding - dependent manner in BCR/ABL-expressing cells is the transcriptional repressor Gfi-1. We show here that C/EBPα 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/EBPα. 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/EBPα required for its proliferation and survival-inhibitory effects in BCR/ABL-expressing cells.
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U2 - 10.1158/0008-5472.CAN-10-1667
DO - 10.1158/0008-5472.CAN-10-1667
M3 - Article
C2 - 20924107
AN - SCOPUS:78049288554
SN - 0008-5472
VL - 70
SP - 7949
EP - 7959
JO - Cancer Research
JF - Cancer Research
IS - 20
ER -