Leukemogenic AML1-ETO fusion protein upregulates expression of connexin 43: the role in AML 1-ETO-induced growth arrest in leukemic cells.
AML1-ETO, a fusion protein generated by the chromosomal translocation t(8;21), is frequently associated with acute myeloid leukemia (AML). In addition to blocking differentiation, AML1-ETO is also shown to induce growth arrest in AML cells, which is unfavorable for leukemogenesis harboring the t(8;21) translocation. However, its precise mechanism is still unclear. Here we provide the first demonstration that the conditional expression of AML1-ETO by the ecdysone-inducible system dramatically increases the expression of connexin 43 (CX43), together with growth arrest at G1 phase in leukemic U937 cells. We also show that the CX43 induction inhibits the proliferation of U937 cells at G1 phase, while the suppression of CX43 expression by small interfering RNA (siRNA) effectively overcomes the growth-inhibitory effect of AML1 -ETO in leukemic cells. Furthermore, either AML1-ETO or CX43 induction elevates cell-cycle negative regulator P27(kip1) protein by inhibiting its degradation, which is antagonized by siRNA against CX43. Taken together, our data indicate that CX43 plays a role in AML1-ETO-induced growth arrest possibly through the accumulation of P27(kip1) protein. The potential mutation or/and epigenetic alterations of CX43 and its related gene(s) deserve to be explored in AML1-ETO-positive AML patients.
Li
Xi
X
Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine (SJTU-SM), Shanghai, China.
Xu
Ya-Bei
YB
Wang
Qiong
Q
Lu
Ying
Y
Zheng
Ying
Y
Wang
Ying-Chao
YC
Lübbert
Michael
M
Zhao
Ke-Wen
KW
Chen
Guo-Qiang
GQ
D001483:Base Sequence; D002453:Cell Cycle; D045744:Cell Line, Tumor; D002891:Chromosomes, Human, Pair 21; D002898:Chromosomes, Human, Pair 8; D018031:Connexin 43 / Q000235:genetics*; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics* / Q000378:metabolism; D017931:DNA Primers; D006801:Humans; D015470:Leukemia, Myeloid, Acute; D008969:Molecular Sequence Data; D015514:Oncogene Proteins, Fusion / Q000235:genetics* / Q000378:metabolism; D034741:RNA, Small Interfering; D000075142:RUNX1 Translocation Partner 1 Protein; D011993:Recombinant Fusion Proteins / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014178:Translocation, Genetic; D020298:U937 Cells
C107844:AML1-ETO fusion protein, human; D018031:Connexin 43; D050676:Core Binding Factor Alpha 2 Subunit; D017931:DNA Primers; D015514:Oncogene Proteins, Fusion; D034741:RNA, Small Interfering; D000075142:RUNX1 Translocation Partner 1 Protein; D011993:Recombinant Fusion Proteins