Mitogenic Cytokines Promote Apoptosis

Abstract

Successful cell proliferation relies on the activation of genes involved in cell cycle progression and concurrent inhibition of the function of tumor suppressor genes. In addition, there is a need to maintain the viability in proliferating cells. In the absence of cell viability factors cell cycle progression is intrinsically linked to programmed cell death through apoptosis. Whereas much attention has been focused on the molecular description of cell cycle machinery and the apoptotic pathway, less attention has been paid to the mechanisms for maintenance of the cell viability while cells are progressing through the cell cycle. The interaction of mitogenic cytokines with their cognate receptors promotes entry to the S-phase of cell cycle. It has also been suggested that cytokines could directly provide cell survival signals based on the observations that cytokine withdrawal leads to apoptosis. However, it is not clear whether the mitogenic activities and the survival effects of these cytokines are exerted by a single biochemical mechanism or carried out through separate signaling pathways. It is, thus, important to establish whether the survival effects of cytokines are achieved directly or by synergizing with the action of survival factors present in the environment such as interstitial fluid or blood in vivo or culture medium in vitro. We have addressed this question by stimulating cells with cytokines in the presence or absence of exogenous serum in vitro. When incubated with cytokines in serum-free medium, several cell types underwent apoptosis, a phenomenon called cytokine-promoted apoptosis. Interestingly, we found that serum is the principle activator of the cell survival gene, Bcl-2; while mitogenic cytokines increase the expression of Bax. In this review, we discuss the relevance of cytokine-promoted apoptosis to the maintenance of cellular homeostasis during development and tumorigenesis.

Apoptosis, the main mechanism of programmed cell death, is a gene-directed process responsible for the elimination of excessive cells during development and detrimental cell types in pathophysiological situations (Wyllie et al., 1980). Aberrant apoptosis has been implicated in the etiology of cancer and the process of autoimmunity (Hale et al., 1996). It is also involved in the progression of some degenerative diseases as well as the evolution of drug resistance in tumors (Hickman, 1992). Deregulated expression of genes such as Bcl-2, loss of p53 expression, and autocrine activation of either apoptotic or antiapoptotic signal transduction pathways may all contribute to pathological apoptosis (McConkey et al., 1996).

Cell proliferation requires the modulation of at least two sets of genes: those that activate mitosis and those that maintain cell survival. The modulation of these genes is required to terminate cell cycle brakes, to activate cell cycle machinery, and to promote cell survival (Meikrantz and Schlegel, 1995). Much is known about the mechanisms of cell cycle promotion, the signals that regulate cell viability during cell cycle are yet to be determined.

Protooncogenes and tumor suppressor genes control and regulate cell cycle progression. In addition, both oncogenes and tumor suppressor genes play fundamental roles in the regulation of the pathways leading to programmed cell death (Chiarugi and Ruggiero, 1996). We have shown that the protooncogene c-Myc is required for activation-induced apoptosis in T cell hybridomas (Shi et al., 1992). Ectopic expression of Myc enhances cell cycle progression and, at the same time, promotes apoptosis of the cycling cells (Evan et al., 1992; Askew et al., 1993). It has also been shown that cyclin A and the CDK kinase inhibitor, p27, play fundamental roles in anti-IgM-induced apoptosis in B-cell lymphomas (Ezhevsky et al., 1996). This strongly suggests that cell cycle progression and apoptosis are tightly correlated, a notion which could have important implications in the understanding of the basic mechanisms regulating apoptosis. In this review, we explore the relationship between apoptosis and cell cycle progression by focusing on the recent studies in cytokine-promoted apoptosis, which will be important for the elucidation of the mechanisms by which normal cells manage to proliferate, and transformed cells undergo aberrant growth during tumorigenesis.