BBC3

BBC3 Background

The BBC3 gene encodes for Bcl-2-binding component 3 (BBC3) protein in humans that belongs to one type of PUMA (p53 upregulated modulator of apoptosis) identified through yeast two-hybrid screening ^[1]. BBC3 gene is a novel BH3-only protein-encoding gene isolated by screening a human lymphocyte cDNA library ^[1], and the other two are cDNA clones encoding Bik and Bad, previously identified BH3-only proteins that bind to Bcl-2. BBC3 protein contains two functional domains: the BH3 domain that is required for interactions with Bcl-2-like proteins such as Bcl-2 ＆ Bcl-XL ^[2][3] and a C-terminal mitochondria-localization signal (MLS) domain ^[4]. Jia-wen Han et al. demonstrated that BBC3 functions to promote apoptosis in a mechanistically similar fashion to previously characterized BH3-only proteins Bik and Bad by observing the BH3-dependent dimerization and pro-apoptotic activities of BBC3 ^[5]. The mechanism process is that upon activation, the BH3-only proteins can activate BAX and BAK, thereby triggering cytochrome c release and apoptosis. They also indicated that BBC3 is a direct transcriptional target of p53 because of p53 transactivated BBC3 through consensus p53 binding sites within the BBC3 promoter region ^[5]. Additionally, BBC3 mRNA was induced by p53-independent apoptotic stimuli, including dexamethasone treatment of thymocytes and serum deprivation of tumor cells ^[5]. Growth factors with anti-apoptotic activity inhibit BBC3 expression ^[5]. The inhibition of BBC3 expression mediated by the IGF-1 receptor may provide an additional, sustained anti-apoptotic signal by reducing the effective levels of BH3 in cells. Dysregulation of the mechanisms that normally control the transcription of BBC3 may contribute to the evolution and/or survival of tumor cells. The loss of p53 function may prevent the activation of BBC3 that would normally follow DNA damage.

[1] Han J, Flemington C, et al. Expression of bbc3, a pro-apoptotic BH3-only gene, is regulated by diverse cell death and survival signals [J]. Proc Natl Acad Sci USA 98: 11318-11323.
[2] Nakano K, Vousden KH. PUMA, a novel proapoptotic gene, is induced by p53 [J]. Mol Cell, 2001, 7: 683-694.
[3] Yu J, Zhang L, et al. PUMA induces the rapid apoptosis of colorectal cancer cells [J]. Mol Cell, 2001, 7: 673-682.
[4] Yu J, Wang Z, et al. PUMA mediates the apoptotic response to p53 in colorectal cancer cells [J]. Proc Natl Acad Sci USA, 2003, 100: 1931-1936.
[5] Jia-wen Han, Cathy Flemington, et al. Expression of bbc3, a pro-apoptotic BH3-only gene, is regulated by diverse cell death and survival signals [J]. PNAS September 25, 2001 98 (20) 11318-11323.