The novel primary response gene MyD118 and the proto-oncogenes myb, myc, and bcl-2 modulate transforming growth factor beta 1-induced apoptosis of myeloid leukemia cells.

Abstract

Cell numbers are regulated by a balance among proliferation, growth arrest, and programmed cell death. A profound example of cell homeostasis, controlled throughout life, is the complex process of blood cell development, yet little is understood about the intracellular mechanisms that regulate blood cell growth arrest and programmed cell death. In this work, using transforming growth factor beta 1 (TGF beta 1)-treated M1 myeloid leukemia cells and genetically engineered M1 cell variants, the regulation of growth arrest and apoptosis was dissected. Blocking of early expression of MyD118, a novel differentiation primary response gene also shown to be a primary response gene induced by TGF beta 1, delayed TGF beta 1-induced apoptosis, demonstrating that MyD118 is a positive modulator of TGF beta 1-mediated cell death. Elevated expression of bcl-2 blocked the TGF beta 1-induced apoptotic pathway but not growth arrest induced by TGF beta 1. Deregulated expression of either c-myc or c-myb inhibited growth arrest and accelerated apoptosis, demonstrating for the first time that c-myb plays a role in regulating apoptosis. In all cases, the apoptotic response was correlated with the level of MyD118 expression. Taken together, these findings demonstrate that the primary response gene MyD118 and the c-myc, c-myb, and bcl-2 proto-oncogenes interact to modulate growth arrest and apoptosis of myeloid cells.

MyD genes in negative growth control

“…Furthermore, activation of an inducible MyD118 transgene in hematopoietic cells was observed to result in apoptotic M1 cell death (unpublished). Blocking the expression of MyD118 in M1 cells by an antisense vector was shown to impair TGFb induced cell death (Selvakumaran et al, 1994a). Furthermore, blocking TGF-b induced apoptosis in M1 cells due to ectopic expression of bcl-2, was associated with down regulation of MyD118 transcripts; in contrast, deregulated expression of c-myc or c-myb in M1, abrogating TGF-b-induced growth arrest and accelerating apoptosis, was associated with marked elevations in the level of MyD118 transcripts (Selvakumaran et al, 1994a).…”

“…Blocking the expression of MyD118 in M1 cells by an antisense vector was shown to impair TGFb induced cell death (Selvakumaran et al, 1994a). Furthermore, blocking TGF-b induced apoptosis in M1 cells due to ectopic expression of bcl-2, was associated with down regulation of MyD118 transcripts; in contrast, deregulated expression of c-myc or c-myb in M1, abrogating TGF-b-induced growth arrest and accelerating apoptosis, was associated with marked elevations in the level of MyD118 transcripts (Selvakumaran et al, 1994a). On the other hand, Gadd45 has been implicated in p53-mediated G1 cell cycle arrest following DNA damage (Kastan et al, 1992).…”

“…In contrast, Gadd45, but not MyD118 is induced upon p53 mediated apoptosis. (Guillouf et al, 1998;Miyashita et al, 1994;Selvakumaran et al, 1994a;Zhan et al, 1994). Still di erent, both MyD118 and Gadd45 are induced upon methyl methanesulfonate (MMS) induced apoptosis (Vairapandi et al, 1996).…”

Inactivation of a c-Myb/estrogen receptor fusion protein in transformed primary cells leads to granulocyte/macrophage differentiation and down regulation of c-kit but not c-myc or cdc2

“…Because Myb can also inhibit the di erentiation of hemopoietic cells (Selvakumaran et al, 1994;Todokoro et al, 1988;Yanagisawa et al, 1991;Clarke et al, 1988), it has been postulated that the e ect of Myb on cellular proliferation may be due to the regulation of c-myc transcription. Indeed, transactivation by Myb of the cmyc promoter (Evans et al, 1990;Nakagoshi et al, 1992;Zobel et al, 1992) and in one case, endogenous c-myc (Evans et al, 1990) has been reported.…”

Induction of apoptosis in U937 human leukemia cells by suberoylanilide hydroxamic acid (SAHA) proceeds through pathways that are regulated by Bcl-2/Bcl-XL, c-Jun, and p21CIP1, but independent of p53

“…HL-60 human promyelocytic leukemia cells induced to undergo maturation by retinoic acid ultimately die an apoptotic death, although as a relatively late event (Martin et al, 1990). However, di erentiation and apoptosis are mutually exclusive in other systems (Selvakumaran et al, 1994). Moreover, dysregulated maturation of U937 human leukemia cells (e.g., following enforced expression of protein kinase C-z) leads to apoptosis rather than di erentiation after treatment with phorbol myristate acetate (PMA) (de Vente et al, 1995).…”