Expression of bbc3 , a pro-apoptotic BH3-only gene, is regulated by diverse cell death and survival signals

Abstract

BH3-only proteins function at a proximal point in a conserved cell death pathway by binding, through their BH3 domains, to other Bcl-2 family members and triggering mitochondrial events associated with apoptosis. Here, we describe a strongly pro-apoptotic BH3-only protein, designated Bbc3, whose expression increases in response to diverse apoptotic stimuli. bbc3 mRNA levels were induced by exposure to DNA-damaging agents and by wild-type p53, which mediates DNA damage-induced apoptosis. p53 transactivated bbc3 through consensus p53 binding sites within the bbc3 promoter region, indicating that bbc3 is a direct target of p53. Additionally, bbc3 mRNA was induced by p53-independent apoptotic stimuli, including dexamethasone treatment of thymocytes, and serum deprivation of tumor cells. Insulin-like growth factor-1 and epidermal growth factor, growth factors with broad anti-apoptotic activity, were each sufficient to suppress Bbc3 expression in serum-starved tumor cells. These results suggest that the transcriptional regulation of bbc3 contributes to the transduction of diverse cell death and survival signals.

Characterisation of p53 status at the gene, chromosomal and protein levels in oesophageal adenocarcinoma

“…Mitogen-activated protein kinase kinase (MAP2K) is a member of the MAP kinase family, and mediates a cellular response to environmental stresses and proinflammatory cytokines through signal transduction cascades. bcl2-binding component 3 (BBC3) is a mediator of p53-associated apoptosis and although its expression in human malignancies is relatively unexplored, suppression might be expected to enhance the survival of neoplastic cells (Han et al, 2001). As the RNA samples examined were pooled, it is possible that the expression of these genes were lost in a single case and not in the others, hence resulting in a slight overall reduction.…”

Frequent loss of expression of the pro-apoptotic protein Bim in renal cell carcinoma: evidence for contribution to apoptosis resistance

“…Puma and Noxa can both participate in the DNAdamage response and might therefore be expected to contribute to sensitivity to UV-and adriamycin-induced apoptosis in RCC. Both are target genes of p53 and are upregulated through p53 (Oda et al, 2000;Han et al, 2001;Nakano and Vousden, 2001). Although most RCC lines contain intact p53 and respond to DNA damage with p53 upregulation, p53 has been found to be unable to upregulate p53-dependent reporters or its target gene p21 (Gurova et al, 2004).…”

Transcriptional upregulation of PUMA modulates endoplasmic reticulum calcium pool depletion-induced apoptosis via Bax activation

“…[1][2][3] It is a direct transcriptional target of p53 that is also regulated by DNA damaging agents in a p53-dependent manner and has also been found to be regulated in response to serum withdrawal as well as treatments with dexamethasone, tunicamycin and thapsigargin (TG). [3][4][5] PUMA encodes a BH3 only domain proapoptotic protein that localizes to mitochondria and interacts with antiapoptotic Bcl-2 and Bcl-X L (1)(2)(3).…”

“…[1][2][3] It is a direct transcriptional target of p53 that is also regulated by DNA damaging agents in a p53-dependent manner and has also been found to be regulated in response to serum withdrawal as well as treatments with dexamethasone, tunicamycin and thapsigargin (TG). [3][4][5] PUMA encodes a BH3 only domain proapoptotic protein that localizes to mitochondria and interacts with antiapoptotic Bcl-2 and Bcl-X L (1)(2)(3). It is now well established that the tumor suppressor p53 predominantly functions as a transcription factor and mediates its effects by inducing growth arrest and/or apoptosis (reviewed in Sheikh and Fornace Jr, 6 Vousden and Lu, 7 and Hofseth et al 8 ).…”