Modulation of bcl-2 and p27 in human primitive proliferating hematopoietic progenitors by autocrine TGF-beta1 is a cell cycle-independent effect and influences their hematopoietic potential.
Primitive, proliferating hematopoietic progenitors (defined as cytokine low-responding primitive progenitors; CLRPP), isolated from human CD34+ cells, expressed endoglin (CD105) and produced transforming growth factor-beta1 (TGF-beta1). Culture of CLRPP in serum-free conditions with anti-TGF-beta1 monoclonal antibody produced a substantial decrease in bcl-2 protein/RNA levels and a significant reduction of cloning and long-term culture-initiating cell (LTC-IC) activities. GATA-1 and PU.1 RNA levels were significantly up-regulated in anti-TGF-beta1-treated CLRPP, which generated an increased number of cells expressing CD15/CD11b/glycophorin-A. The described effects of TGF-beta1 neutralization were observed in the absence of any relevant effect on cell cycle; number of cell divisions; p53, c-myc, and p21 RNA levels; bcl-xL and bax protein levels; and c-myc/p16/p21/p107/Rb cell cycle-related protein levels. A relevant increase in p27 protein levels was observed in anti-TGF-beta1-treated CLRPP, suggesting a role for p27 in the regulation of the hematopoietic potential. The present study on human progenitors and previously reported data on TGF-beta1 knockout mice suggest that, at the autocrine level, the cell cycle inhibitor TGF-beta1 plays an important role in regulating the survival and differentiation of primitive proliferating hematopoietic progenitors by cell cycle-independent mechanisms.
Pierelli
L
L
Cattedra di Ematologia, Istituto di Ostetricia e Ginecologia, Universita' Cattolica del Sacro Cuore, Rome, Italy.
Marone
M
M
Bonanno
G
G
Mozzetti
S
S
Rutella
S
S
Morosetti
R
R
Rumi
C
C
Mancuso
S
S
Leone
G
G
Scambia
G
G
D000818:Animals; D019898:Autocrine Communication; D002453:Cell Cycle / Q000502:physiology; D018797:Cell Cycle Proteins; D002454:Cell Differentiation / Q000502:physiology; D050760:Cyclin-Dependent Kinase Inhibitor p27; D006410:Hematopoiesis; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000502:physiology*; D006801:Humans; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000502:physiology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000502:physiology*; D025521:Tumor Suppressor Proteins
C493961:Cdkn1b protein, mouse; D018797:Cell Cycle Proteins; D008869:Microtubule-Associated Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D016212:Transforming Growth Factor beta; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27