The level of the tissue‐specific factor GATA‐1 affects the cell‐cycle machinery

Abstract

GATA-1 is a tissue-specific DNA-binding protein containing two zinc-finger-like domains. It is expressed predominantly in erythrocytes. Consensus binding sites for GATA-1 have been found in the regulatory elements of all erythroid-specific genes examined. GATA-1 protein is required for erythroid differentiation beyond the proerythroblast stage. In this paper, we demonstrate that the overexpression of GATA-1 in murine erythroleukaemia (MEL) cells alleviates DMSO-induced terminal erythroid differentiation. Hence, there is no induction of globin gene transcription and the cells do not arrest in the G1 phase of the cell cycle. Furthermore, we demonstrate that expression of GATA-1 in non-transformed erythroid precursors also affects their proliferative capacity and terminal differentiation, as assayed by adult globin gene transcription. To gain insight into the mechanism of this effect, we studied the levels and activities of regulators of cell-cycle progression during DMSO-induced differentiation. A decrease in cyclin D-dependent kinase activity was observed during the induction of both control and GATA-1-overexpressing MEL cells. However, cyclin E-dependent kinase activity decreased more than 20-fold in control but less than 2-fold in GATA-1-overexpressing MEL cells upon induction. Thus GATA-1 may exert its effects by regulating cyclin E-dependent kinase activity. We also show that GATA-1 binds to the retinoblastoma protein in vitro, but not to the related protein p107, which may indicate that GATA-1 interacts directly with specific members of the cell-cycle machinery in vivo. We conclude that GATA-1 regulates cell fate, in terms of differentiation or proliferation, by affecting the cell-cycle apparatus.

Graded Levels of GATA-1 Expression Modulate Survival, Proliferation, and Differentiation of Erythroid Progenitors

“…It was previously reported that forced expression of GATA-1 accelerates erythroid differentiation along with the suppression of cell proliferation (22), whereas overexpression of the transcription factor during mouse erythroleukemia cell differentiation shows the opposite effect (14). Ectopic expression of human GATA-1 by retroviral infection into NIH3T3 fibroblasts results in reduced growth rates by prolonging S phase and altering the proliferative growth response to serum (15).…”

“…These reports suggest that GATA-1 participates in the cell cycle control. Physical association of GATA-1 with Rb has been suggested to play a role in this process (14), but it has not been reported which cell cycle-associated molecules might be subjected to the actions of GATA-1 at the mRNA level, in particular during erythroid development. The results shown here suggest that p16…”

“…Erythroid Cells Derived from GATA-1 Mutant ES Cells Accumulate in S Phase-It has been reported that forced expression of GATA-1 alters the length of cell cycle segments (14) and that especially high levels of GATA-1 were found to lengthen S phase in NIH3T3 cells (15). In addition, Cullen et al (16) showed that GATA-1 activity in mouse erythroleukemia cells was low in G 1 phase, peaked in mid-S phase, and then dimin- ished again in G 2 /M phase and showed that the accumulation patterns of GATA-1 protein and mRNA mirrored one another throughout the cell cycle.…”

Tumor necrosis factor alpha-mediated inhibition of erythropoiesis involves GATA-1/GATA-2 balance impairment and PU.1 over-expression

“…In erythropoiesis, the GATA-1 and GATA-2 transcription factors have essential roles, and a quantitative balance in their protein levels is required to achieve erythroid lineage A c c e p t e d M a n u s c r i p t 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 -17 -vivo, inhibits erythroid differentiation [54,55]. In our in vitro culture system, GATA-1, and GATA-2 were both over-expressed, suggesting a deregulation of the balance between GATA-1 and GATA-2 after TNF treatment.…”

Enforced Expression of GATA-3 During T Cell Development Inhibits Maturation of CD8 Single-Positive Cells and Induces Thymic Lymphoma in Transgenic Mice

“…Finally, a more general mechanism might be responsible for the oncogenic effect of GATA-3, since GATA factors have a key role in the regulation of development toward cell division and differentiation via the cell cycle machinery (69). Recently several other GATA family factors have been implicated in various human tumors, e.g., GATA-2 in acute promyelocytic leukemia, acute myeloid leukemia, and myelodysplastic syndrome and GATA-4 in esophageal adenocarcinomas and malignancies of the gonads (70 -72).…”