The bcl-2 Oncogene: Apoptosis and Neoplasia

Abstract

Cloning of the t(14;18) translocation breakpoint resulted in the identification of a new putative oncogene, which mapped to 18q21, termed bcl-2. The t(14;18) resulted in inappropriately high levels of bcl-2 expression in follicular lymphoma. Prospective studies using mice transgenic for a human bcl-2-immunoglobulin minigene, intended to recreate the molecular features of the t(14;18), demonstrated that bcl-2 gene deregulation was oncogenic. Interestingly, overexpression of bcl-2 showed no demonstrable influence on rates of cellular proliferation. Rather, bcl-2 was found to extend cellular viability by blocking apoptosis. Recent studies with other oncogenes and tumor suppressor genes, such as c-myc and p53, have demonstrated that the deregulation of apoptosis may be of general significance in the development of multiple types of cancer and appears to be a critical event during multistep carcinogenesis. The selective induction of apoptosis in tumor cell populations is now being considered in the design of novel therapeutic interventions.

Androgens repress Bcl-2 expression via activation of the retinoblastoma (RB) protein in prostate cancer cells

“…It is also possible, but not necessarily mutually exclusive that androgen ablation may reset the regulatory effect of androgens on Bcl-2 expression in androgen-responsive cells. In fact, levels of Bcl-2 transcripts increase in the rat prostate following castration (McDonnell et al, 1992). Moreover, this increase is abrogated in castrated rats that receive testosterone.…”

“…One of the antiapoptotic factors that favors the survival of androgen-refractory prostate cancer cells may involve overexpression of Bcl-2 (McDonnell et al, 1992;Colombel et al, 1993;Krajewska et al, 1996). Bcl-2 protein is expressed intensely in 77% of androgen-refractory prostate tumors compared to 32% in androgen-sensitive tumors (McDonnell et al, 1992(McDonnell et al, , 1997Westin et al, 1995).…”

Mechanisms of apoptosis by c-Myc

“…Apoptosis can stanch such proliferation but apoptotic mechanisms are progressively eliminated during neoplastic progression (Williams, 1991). Substantial clinical evidence argues that this progressive elimination is a crucial step in malignant conversion, for example, in the progression of prostate carcinoma to hormone independence (Kyprianou et al, 1990;McDonnell et al, 1992;BraÈ ndstroÈ m et al, 1994;Ra o et al, 1995). This is not due to loss or inactivation of the basic machinery of apoptosis, which remains intact even in advanced malignancies (Martin and Green, 1995).…”

The c-Myc-interacting adaptor protein Bin1 activates a caspase-independent cell death program

“…Our ®ndings suggest that loss of Bin1 may eliminate one mechanism which can limit the consequences of inappropriate activation of c-Myc or other oncogenes. Suicide mechanisms are progressively eliminated during neoplastic progression (Williams, 1991), and in invasive breast cancers and metastatic prostate cancers where Bin1 losses occur frequently (Ge et al, 2000a,b) there is strong evidence that loss of cell suicide capacity corresponds with malignant conversion (Kyprianou et al, 1990(Kyprianou et al, , 1991McDonnell et al, 1992). However, malignant conversion is associated generally with altered adhesive capabilities that facilitate invasion and metastasis.…”