Journal
MOLECULAR AND CELLULAR BIOLOGY
Volume 24, Issue 15, Pages 6751-6762Publisher
AMER SOC MICROBIOLOGY
DOI: 10.1128/MCB.24.15.6751-6762.2004
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Funding
- NCI NIH HHS [R01 CA031615, R01 CA 31615] Funding Source: Medline
- NIDDK NIH HHS [R01 DK 49855, R01 DK049855] Funding Source: Medline
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Members of the homeobox family of transcription factors are major regulators of hematopoietic. Overexpression of either HOXB4 or HOXA9 in primitive marrow cells enhances the expansion of hematopoietic stem cells (HSCs). However, little is known of how expression or function of these proteins is regulated during hematopoiesis under physiological conditions. In our previous studies we demonstrated that thrombopoietin (TPO) enhances levels of HOXB4 mRNA in primitive hematopoietic cells (K. Kirito, N. Fox, and K. Kaushansky, Blood 102:3172-3178, 2003). To extend our studies, we investigated the effects of TPO on HOXA9 in this same cell population. Although overall levels of the transcription factor were not affected, we found that TPO induced the nuclear import of HOXA9 both in UT-7/TP6 cells and in primitive Sca-1(+)/c-kit(+)/Gr-1(-) hematopoietic cells in a mitogen-activated protein kinase-dependent fashion. TPO also controlled MEIS1 expression at mRNA levels, at least in part due to phosphatidylinositol 3-kinase activation. Collectively, TPO modulates the function of HOXA9 by leading to its nuclear translocation, likely mediated by effects on its partner protein MEIS1, and potentially due to two newly identified nuclear localization signals. Our data suggest that TPO controls HSC development through the regulation of multiple members of the Hox family of transcription factors through multiple mechanisms.
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