Environmental Chemical-Induced Pro/Pre-B Cell Apoptosis: Analysis of c-Myc, p27Kip1, and p21WAF1 Reveals a Death Pathway Distinct from Clonal Deletion

Abstract

Polycyclic aromatic hydrocarbons (PAH) are common environmental pollutants that suppress the immune system in part by inducing pro/pre-B cell apoptosis. The PAH-induced death signaling pathway resembles the signaling cascade activated during clonal deletion and modeled by B cell receptor cross-linking or by dexamethasone exposure of immature surface Ig+ B cells in that apoptosis is mediated by NF-κB down-regulation. Because a PAH-induced, clonally nonrestricted deletion of B cells would have important implications for B cell repertoire development, the nature of the PAH-induced intracellular death signal was studied further. Particular emphasis was placed on the roles of growth arrest and c-Myc, p27Kip1, and p21WAF1 expression, because all of these elements contribute to clonal deletion. As in clonal deletion models, and as predicted by the down-regulation of NF-κB, PAH-induced death of pro/pre-B cells was at least partially dependent on c-Myc down-regulation. Furthermore, whereas dexamethasone induced a G0/G1 cell cycle arrest, PAH had no effect on pro/pre-B cell growth, indicating that growth arrest and apoptosis occur by separable signaling pathways in this early phase of B cell development. Finally, in contrast to clonal deletion, PAH-induced pro/pre-B cell death was not dependent on p27Kip1 or p21WAF1 up-regulation but did coincide with p53 induction. These results distinguish the PAH-induced apoptosis pathway from that activated during clonal deletion and indicate that signaling cascades leading to growth arrest and/or apoptosis in pro/pre-B cells differ from those active at later B cell developmental stages.

The aryl hydrocarbon receptor constitutively represses c-myc transcription in human mammary tumor cells

“…That this increase in endogenous mRNA or protein was not as dramatic as the increase in c-myc reporter activity (Figure 7c) may reflect post-transcriptional and post-translational factors, which limit steady-state c-myc mRNA and c-Myc protein levels. Nevertheless, a two-fold increase in c-Myc is generally sufficient to effect biologic changes, at least in normal cells (Ryu et al, 2003).…”

“…Increases in endogenous or ectopic c-Myc expression can either enhance (Ruggero et al, 2004;Wang et al, 2004b) or inhibit apoptosis (Bellas and Sonenshein, 1999;Ryu et al, 2003), depending on the cell type studied. In primary mammary tumors and in Hs578T cells, c-Myc tends to induce apoptosis (Chen et al, 1998;Liao and Dickson, 2003).…”

“…These results beg the question of what function the AhR is performing in these cells. This question is all the more significant in light of several studies associating AhR activation with cell growth (Ma and Whitlock, 1996;Weiss et al, 1996;Ge and Elferink, 1998;Puga et al, 2000Puga et al, , 2002Abdelrahim et al, 2003;Ohtake et al, 2003;Thomsen et al, 2004) or apoptosis regulation (Yamaguchi et al, 1997;Matikainen et al, 2001Matikainen et al, , 2002Ryu et al, 2003;Caruso et al, 2004). Indeed, the demonstrable influence of the AhR on at least tumor cell growth has motivated the targeting of this receptor/ transcription factor or its gene targets for cancer therapy (Safe, 2001;Koliopanos et al, 2002;Abdelrahim et al, 2003;Maecker et al, 2003;Zhang et al, 2003).…”

“…Here, we evaluated the potential for the AhR to affect directly transcription of c-myc, an important oncogene that can regulate cell growth (Pelengaris and Khan, 2003) and apoptosis (Wu et al, 1996;Thompson, 1998;Ryu et al, 2003) and which is dysregulated in many tumor types including breast cancers (Escot et al, 1986;Leder et al, 1986;Borg et al, 1992;Pelengaris and Khan, 2003). AhRmediated regulation of c-myc seemed plausible given the presence of six AREs within a 3.2 kb region of the human c-myc promoter.…”

Environmental Chemical-Induced Bone Marrow B Cell Apoptosis: Death Receptor-Independent Activation of a Caspase-3 to Caspase-8 Pathway

“…In these systems, contributions of nuclear factor-B and c-Myc down-regulation (Wu et al, 1996a,b);p53, p27 Kip1 , and p21 WAF1 up-regulation (Wu et al, 1998); mitochondrial activation (Doi et al, 1999); and protease (calpain, cathepsin, and caspase) activation (Ruiz-Vela et al, 1999) have begun to be defined. Our laboratory has investigated previously whether B lymphocytes earlier in development are similarly susceptible to apoptosis (Yamaguchi et al, 1997a;Mann et al, 1999Mann et al, , 2001Ryu et al, 2003). Because pro-and pre-B cells do not express surface Ig, prototypic polycyclic aromatic hydrocarbons (PAH) such as benzo-[a]pyrene or dimethylbenz [a]anthracene (DMBA) was used to induce apoptosis in these early B cells.…”