@article{bf6088e9e3a540d3a0db5844949aab67,
title = "HOXB4 inhibits cell growth in a dose-dependent manner and sensitizes cells towards extrinsic cues",
abstract = "Ectopic expression of the homeodomain transcription factor HOXB4 expands hematopoietic stem and progenitor cells in vivo and in vitro, making HOXB4 a highly interesting candidate for therapeutic stem cell expansion. However, when expressed at high levels, HOXB4 concomitantly perturbs differentiation and thus likely predisposes the manipulated cells for leukemogenesis. We therefore asked whether the expression level of HOXB4 may be a critical parameter that influences the growth and transformation properties of transduced cells. Using a set of retroviral vectors which covered a 40-fold range of expression levels, we studied the consequences of HOXB4 expression at different levels in the well established Rat-1 fibroblast cell system. HOXB4 transformed Rat-1 fibroblasts beyond a certain threshold level of expression. Further escalation of HOXB4 expression, however, did not enhance transformation. Instead, HOXB4 mediated a dose dependent anti-proliferative effect on Rat-1 and NIH3T3 fibroblasts. This effect was aggravated under reduced serum concentrations and was, at least partially, due to an enhanced sensitivity of HOXB4 overexpressing cells to induction of apoptosis. Based on these results we propose that HOXB4 affects cell growth in a dose-dependent manner by sensitizing cells towards extrinsic signals.",
keywords = "Apoptosis, Fibroblasts, HOXB4, Rat-1, Transformation, c-Myc",
author = "Elke Will and Daniel Speidel and Zheng Wang and Gabriel Ghiaur and Andreas Rimek and Bernhard Schiedlmeier and Williams, {David A.} and Christopher Baum and Wolfram Ostertag and Hannes Klump",
note = "Funding Information: We wish to thank Irene Dornreiter and Carol Little is known about the mechanisms underlying the described activities of HOXB4 Stocking for providing us with the SV40 Large-T in primary cells and cell lines. It has been shown that the DNA-binding activity of this respectively. This work was supported by thecDNA and retroviral expression vector R229, transcription factor is essential for its function.12Thus, one can assume that the observed German Research Foundation (DFG), DFG-grant effects reflect the influence of HOXB4 on the transcription of effector target genes. In WI-1995/1-1 and KL1311/2-3, German Cancer vitro, HOX protein monomers bind to DNA only with low affinity and specificity, which Aid (“Deutsche Krebshilfe”, 10-1763-OS5), the both can be increased by heteromeric complex formation with PBX and MEIS protein European Union (Consert), and an intramural family members.15-17 In vivo, DNA binding can also be altered by modifications such as grant of Cincinnati Childr{\textcopyright}2005 LANDES BIOSCIENCEen{\textquoteright}s Hospital Research phosphorylationor ubiquitination.Nevertheless, present knowledge on HOXB4 does1819 Foundation. not provide a sufficient explanation of its dose-dependent effects on self renewal and differentiation of HSCs. The various effects may reflect the capability of HOXB4 to target different DNA binding sites, similar to what is known from the well studied homeodomain transcription factors in Drosophila, such as Bicoid20 and Caudal.21 In Drosophila, altered concentrations of a single transcription factor can switch the fate of a cell by differential binding to high-or low-affinity binding sites in the promoter region of certain genes, as shown for Dorsal, the homologue of mammalian NF-κB.22 Its additional interaction with",
year = "2006",
month = jan,
day = "1",
doi = "10.4161/cc.5.1.2304",
language = "English (US)",
volume = "5",
pages = "14--22",
journal = "Cell Cycle",
issn = "1538-4101",
publisher = "Landes Bioscience",
number = "1",
}