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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 14-22 |
| Number of pages | 9 |
| Journal | Cell cycle (Georgetown, Tex.) |
| Volume | 5 |
| Issue number | 1 |
| State | Published - Jan 1 2006 |
| Externally published | Yes |
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Keywords
- Apoptosis
- c-Myc
- Fibroblasts
- HOXB4
- Rat-1
- Transformation
ASJC Scopus subject areas
- Cell Biology
- Biochemistry
- Molecular Biology
Cite this
HOXB4 inhibits cell growth in a dose-dependent manner and sensitizes cells towards extrinsic cues. / Will, Elke; Speidel, Daniel; Wang, Zheng; Ghiaur, Gabriel; Rimek, Andreas; Schiedlmeier, Bernhard; Williams, David A.; Baum, Christopher; Ostertag, Wolfram; Klump, Hannes.
In: Cell cycle (Georgetown, Tex.), Vol. 5, No. 1, 01.01.2006, p. 14-22.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - HOXB4 inhibits cell growth in a dose-dependent manner and sensitizes cells towards extrinsic cues
AU - Will, Elke
AU - Speidel, Daniel
AU - Wang, Zheng
AU - Ghiaur, Gabriel
AU - Rimek, Andreas
AU - Schiedlmeier, Bernhard
AU - Williams, David A.
AU - Baum, Christopher
AU - Ostertag, Wolfram
AU - Klump, Hannes
PY - 2006/1/1
Y1 - 2006/1/1
N2 - 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.
AB - 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.
KW - Apoptosis
KW - c-Myc
KW - Fibroblasts
KW - HOXB4
KW - Rat-1
KW - Transformation
UR - http://www.scopus.com/inward/record.url?scp=33645291810&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=33645291810&partnerID=8YFLogxK
M3 - Article
C2 - 16357528
AN - SCOPUS:33645291810
VL - 5
SP - 14
EP - 22
JO - Cell Cycle
JF - Cell Cycle
SN - 1538-4101
IS - 1
ER -