ΔFosB, but not FosB, induces delayed apoptosis independent of cell proliferation in the Rat1a embryo cell line

Abstract

The fates of Rat1a cells expressing FosB and DFosB as fusion proteins (ER-FosB, ER-DFosB) with the ligand binding domain of human estrogen receptor were examined. The binding of estrogen to the fusion proteins resulted in their nuclear translocation and triggered cell proliferation, and thereafter delayed cell death was observed only in cells expressing ER-DFosB. The proliferation of Rat1a cells, but not cell death triggered by ER-DFosB, was completely abolished by butyrolactone I, an inhibitor of cyclinedependent kinases, and was partly suppressed by antisense oligonucleotides against galectin-1, whose expression is induced after estrogen administration. The cell death was accompanied by the activation of caspase-3 and -9, the fragmentation of the nuclear genome and cytochrome c release from the mitochondria, and was suppressed by zDEVD-fmk and zLEHD-fmk but not zIETD-fmk. The cell death was not suppressed by exogenous His-PTD-Bcl-x L at all, suggesting involvement of a Bcl-x L -resistant pathway for cytochrome c release.

Selective induction of ΔFosB in the brain after transient forebrain ischemia accompanied by an increased expression of galectin-1, and the implication of ΔFosB and galectin-1 in neuroprotection and neurogenesis

“…We recently identified galectin-1 to be a secretory factor whose expression is induced by DFosB in embryonic cell lines, [20][21][22] and we herein showed the expression of galectin-1 to be significantly upregulated in the embryonic cortical cells by either FosB or DFosB, as well as in the hippocampus after ischemia. Furthermore, our data also indicate that galectin-1, as a secretory factor from FosB-or DFosB-expressing cells, appears to promote the proliferation of embryonic cortical cells.…”

“…We previously demonstrated that an artificial expression of DFosB, and to a lesser extent FosB, triggers DNA replication and cell division in quiescent fibroblast cells in the absence of serum. [18][19][20][21] Furthermore, neurogenesis in the adult mammalian brain has been proven to occur in the SVZ and DG of the hippocampus, and it is likely to be promoted by stress such as ischemic insult.…”

“…Since fosB gene products possess the potential to initiate proliferation of quiescent cells, [18][19][20][21][22] we hypothesize that DFosB induces the proliferative activation of neuronal stem cells or precursor cells in the ischemic brain. Figure 2 DFosB is selectively expressed in the ependymal cells within the LV wall after transient forebrain ischemia.…”

“…[14][15][16][17] We previously found that DFosB, and to a lesser extent FosB, triggers one round of proliferation in the quiescent rat embryo cell lines rat 3Y1 and rat 1a followed by a different cell fate such as morphological alteration or delayed cell death, respectively. [18][19][20][21][22] We have also shown that the expression of galectin-1, one of the major b-galactoside sugar-binding lectins, is induced by DFosB in those cells, and it is required for the proliferative activation of quiescent rat 1a cells by DFosB, 21 thus indicating that galectin-1 is one of the functional targets of DFosB to modulate the cell fate, thus suggesting that DFosB, together with galectin-1, may play a critical role in determining the cell fate observed in the damaged brain.…”

“…20,21 We examined the expression of galectin-1 in the cortical cells after FosB or DFosB expression, since galectin-1 is known to be a secretory Figure 7 DNA synthesis in adenovirus-infected rat embryonic cortical cells. Rat embryonic cortical cells were infected with each recombinant adenovirus encoding EGFP alone, FosB-EGFP and DFosB-EGFP, as indicated on the left side, and were cultured in the presence of B27 supplement and 10 mM BrdU for 3 days.…”