Genetics of Apoptosis

activates the downstream executioner caspases, without involvement of the
mitochondrial pathway (Scaffidi et al., 1998).

4.

The Bcl-2 protein family

The founder protein of the Bcl-2 (B-cell lymphoma gene 2) family was identified as
a proto-oncogen in follicular B-cell lymphoma. In the lymphoma cells, the Bcl-2
protein was overexpressed, rendering the cells resistant to apoptosis. The gene was
found at the translocation site between chromosomes 18 and 14, resulting in it being
under the expression control of the immunoglobulin heavy chain intron enhancer
(Tsujimoto et al., 1985). Subsequent studies identified Bcl-2 as a mammalian
homolog of the apoptosis repressor ced-9 in C. elegans (Hengartner and Horvitz,
1994a). Bax (Bcl-2 associated protein X) was the first proapoptotic family member
to be identified through coimmunoprecipitation with Bcl-2 (Oltvai et al., 1993). The
family now contains over 20 members (Figure 2 ). Although the overall amino-acid
sequence homology is fairly low, the proteins contain up to four highly conserved
domains, referred to as the Bcl-2 homology domains, or BH domains. The BH
domains are essential for interactions between the proteins and for their activities
(Yin et al., 1994; Chittenden et al., 1995; Hunter and Parslow, 1996; Hirotani et al.,
1999). In addition, some members have a hydrophobic C-terminal domain, thought
to be involved in targeting the proteins to lipid membranes (Figure 3).

Figure 2. The Bcl-2 protein family.

The Bcl-2 proteins can be divided into antiapoptotic and proapoptotic members.

The proapoptotic proteins can be further subdivided into multidomain and ‘BH3-

domain-only’ members.

MITOCHONDRIA IN APOPTOSIS INDUCTION 125