Physical and functional interaction of Runt-related protein 1 with hypoxia-inducible factor-1α

Abstract

Angiogenesis and hematopoiesis are closely linked and interactive with each other, but few studies were given to identify possible links between angiogenesis-promoting proteins and hematopoiesis-related transcription factors. Here we investigated the potential relationship of oxygensensitive a-subunit of angiogenesis-related hypoxiainducible factor-1a (HIF-1a) with Runt-related protein 1 (Runx1, also known as acute myeloid leukemia-1, AML-1), an important hematopoietic transcription factor. The results demonstrated that Runx1 and HIF-1a proteins directly interacted with each other to a degree, in which Runt homology domain of Runx1 was mainly involved. Leukemia-related abnormal Runx1 fusion protein AML1-ETO, which fuses the N-terminal 177 amino acid residues of the Runx1 protein in frame to ETO (eight-twenty-one) protein, also interacted with HIF-1a protein with greater ability than Runx1 itself. More intriguingly, Runx1 overexpression inhibited DNA-binding and transcriptional activity of HIF-1 protein with reduced expression of HIF-1-targeted genes such as vascular endothelial growth factor, while silence of Runx1 expression by specific small interfering RNA significantly increased transcriptional activity of HIF-1 protein, suggesting that Runx1 inhibited transcription-dependent function of HIF-1. Vice versa, HIF-1a increased DNA-binding ability and transcriptional activity of Runx1 protein. All these data would shed new insight to understanding Runx1 and HIF-1a-related hematopoietic cell differentiation and angiogenesis.

Runx2 Protein Stabilizes Hypoxia-inducible Factor-1α through Competition with von Hippel-Lindau Protein (pVHL) and Stimulates Angiogenesis in Growth Plate Hypertrophic Chondrocytes

“…In the Runx family, it has been reported that RUNX1 and Runx2 physically interact with HIF-1␣ and regulate the transcription function of HIF-1␣ (37,38). Dual inhibition of Runx2 and HIF-1␣ synergistically aggravate bone formation (39).…”

Sumoylation of hypoxia inducible factor-1α and its significance in cancer

“…Our investigations showed that HIF-1-mediated leukemic cell differentiation is independent of the transcriptional activity of HIF-1 [80]. In short, hypoxia-stabilized HIF-1 interacts with and increases the transcriptional activity of C/EBP and Runt-related protein 1 (Runx1, also named acute myeloid leukemia-1, AML1) [81][82][83]. Therefore, the question of whether sumoylation of HIF-1 contributes to leukemogenesis and leukemic cell differentiation deserves further investigation.…”

Accumulation of hypoxia-inducible factor-1 protein and its role in the differentiation of myeloid leukemic cells induced by all-trans retinoic acid

“…13,14 Furthermore, we previously showed that HIF-1α protein can physically interact with and enhance the transcriptional activity of C/EBPα 17,21 and Runx1. 20 Therefore, although conditional HIF-1α expression and CoCl2 treatment failed to change the levels of these proteins regardless of the presence of 10 -8 M ATRA ( Figure 3A and 4A), we still attempted to understand the potential role of these transcriptional factors in the cooperative differentiation-inducing effect of HIF-1α with ATRA. To this purpose, shRNA specifically targeting PU.1, Runx1 and C/EBPα (named shR-P3, shR-A2 and shR-C2, respectively) were transfected into leukemic U937T clone cells.…”

“…Other targeted sequences have been described previously. 19,20 These shRNA-containing vectors and the negative control pSilencer neo vector were transfected into U937 cells and U937T clone cells using the Gene Pulser Xcellt Eukaryotic System (Bio-Rad, Hercules, CA, USA). Forty-eight hours later, 600 µg/mL of G418 (Sigma-Aldrich) were added to select the stably transfected cells.…”

“…19 Furthermore, HIF-1α protein can interact with C/EBPα and Runx1 proteins and increase their transcriptional activities. 17,20,21 Kim et al found that Tiron, an antioxidant and non-toxic chelator widely used to alleviate acute metal overload, induces differentiation of human HL-60 leukemic cells through increased expression of HIF-1α. 22 In this study we investigated the effects of ATRA on HIF-1α protein in AML cell lines.…”