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.
authors.affiliation: Department of Experimental Hematology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
authors.forename: Elke
authors.initials: E
authors.lastname: Will
authors.forename: Daniel
authors.initials: D
authors.lastname: Speidel
authors.forename: Zheng
authors.initials: Z
authors.lastname: Wang
authors.forename: Gabriel
authors.initials: G
authors.lastname: Ghiaur
authors.forename: Andreas
authors.initials: A
authors.lastname: Rimek
authors.forename: Bernhard
authors.initials: B
authors.lastname: Schiedlmeier
authors.forename: David A
authors.initials: DA
authors.lastname: Williams
authors.forename: Christopher
authors.initials: C
authors.lastname: Baum
authors.forename: Wolfram
authors.initials: W
authors.lastname: Ostertag
authors.forename: Hannes
authors.initials: H
authors.lastname: Klump
mesh_terms: D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation; D005822:Genetic Vectors / Q000235:genetics; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D018398:Homeodomain Proteins; D016271:Proto-Oncogene Proteins c-myc; D014157:Transcription Factors