The estrogen receptor cooperates with the TGF alpha receptor (c-erbB) in regulation of chicken erythroid progenitor self-renewal.

Abstract

A unique combination of growth promoting factors is described that allows growth of large amounts (10(10)‐10(11)) of normal erythroid progenitors from chick bone marrow. These erythroid progenitors express the estrogen receptor (ER) as well as the receptor tyrosine kinase TGF alpha R/c‐erbB. They require both TGF alpha and estradiol for sustained self‐renewal in vitro, but terminally differentiate upon withdrawal of TGF alpha and inactivation of the ER by an antagonist (ICI 164.384). Overexpression of the human ER in erythroblasts devoid of endogenous ER revealed that the hormone‐activated ER alone arrested erythroid differentiation and repressed a large group of erythrocyte genes. When similarly overexpressed, TGF alpha R/c‐erbB inhibited the expression of a distinct, but overlapping, set of genes. The endogenous ER and TGF alpha R/c‐erbB affect erythrocyte gene expression in a similar, but less pronounced fashion. Surprisingly, suppression of ER function by antagonist efficiently inhibited erythroblast transformation by tyrosine kinase oncogenes, suggesting a role of the endogenous ER in leukemogenesis. We speculate that the oncogenes v‐erbB and v‐erbA cooperate in erythroleukemia induction by a mechanism that is employed by TGF alpha R/c‐erbB and ER to regulate normal progenitor self‐renewal in response to external signals.

Multiple mutations contribute to repression by the v-Erb A oncoprotein

“…Some, such as the asparagine to lysine replacement in helix 3, impair T3 binding, and thereby stabilize corepressor recruitment at intermediate T3 levels. In fact, v-/c-Erb A chimeras possessing the v-Erb A lysine at this position confer increased proliferation and a greater resistance to T3-induced differentiation in erythroid cells than do chimeras that possess the c-Erb A Arg (Zenke et al, 1990;Schroeder et al, 1992a). This same mutation, operating together with the C-terminal helix 12 truncation, also conferred on v-Erb A a hormone-resistant enhancement of c-Jun function that has been previously implicated in augmenting fibroblast proliferation (Desbois et al, 1991;Sharif and Privalsky, 1992).…”

The fibroblast growth factor receptor FGFR-4 acts as a ligand dependent modulator of erythroid cell proliferation

“…To prepare TGFa progenitors chicken bone marrow cells were prepared and cultured in modi®ed CFU-E medium essentially as described above, but containing 100 ng/ml SCF, 1 ± 5 ng/ml TGFa (Promega), 10 76 M estrogen and 10 76 M dexamethasone (Sigma; Hayman et al, 1993;Schroeder et al, 1993;Wessely et al, 1997). Homogenous populations of TGFa progenitors were obtained at day 12 ± 14.…”

“…Avian hematopoietic cells provide useful experimental model systems that are well suited to obtain largely homogeneous populations of erythroid progenitors derived from bone marrow. These progenitors can be ampli®ed in vitro as homogenous cell populations to large cell numbers in the presence of speci®c growth factors, such as stem cell factor (SCF) and transforming growth factor type a (TGFa; Hayman et al, 1993;Briegel et al, 1993Briegel et al, , 1996Schroeder et al, 1993;Beug et al, 1995;Dolznig et al, 1995;Steinlein et al, 1995;Wessely et al, 1997). Additionally, by changing the culture conditions and addition of di erentiation factors such progenitors e ectively undergo terminal di erentiation and thereby faithfully recapitulate erythroid cell di erentiation in vitro.…”

Role of Nuclear Matrix in Estrogen Regulated Gene Expression in Human Breast Cancer Cells

“…IN AN ESTROGEN-DEPENDENT MANNER, the estrogen receptor (ER) inhibits erythroid differentiation and expression of erythroid-specific genes in chickens (Schroeder et al, 1993). Histone H5 is a HI-like histone.…”