The relationship between BcI2, Bax and p53: consequences for cell cycle progression and cell death

Abstract

Each cell is under constant surveillance to maintain the integrity of its genome. Genomic lesions in a cell must be repaired before the onset of DNA replication and cell division. In the scenario that the genomic lesion is not repairable, the damaged cells are disposed in an orderly manner known as programmed cell death or apoptosis. Apoptosis and cell cycle progression are two intimately linked phenomena. Uncontrollable cell proliferation perturbs the cellular homeostasis and this can lead to malignancies, as well as organ dysfunction and developmental abnormalities. The biological pathway controlling cell fate is sequentially organized at the molecular level. Recent studies have made important contributions in advancing our knowledge of the mechanisms of cell cycle control and apoptosis regulation. A oncogene-derived protein, Bcl2, confers negative control in the pathway of cellular suicide machinery. A Bcl2-homologous protein, Bax, promotes cell death by competing with Bcl2. While Bax-Bax homodimers act as apoptosis inducers, Bcl2-Bax heterodimer formation evokes a survival signal for the cells. Both Bcl2 and Bax are transcriptional targets for the tumour suppressor protein, p53, which induces cell cycle arrest or apoptosis in response to DNA damage. In all, the coordinate performance of these molecules is crucial for controlling life and death of a cell.

Malathion-induced testicular toxicity is associated with spermatogenic apoptosis and alterations in testicular enzymes and hormone levels in male Wistar rats

“…The reduction of T may be due to the adverse effect of malathion on the rat hypothalamic- [Korsmeyer, 1999;Basu and Haldar, 1998]. Data from this study clearly indicated the apoptotic effect of malathion by increased expression of Bax and decreased Bcl-2.…”

Abnormalities of apoptotic and cell cycle regulatory proteins in distinct histopathologic components of benign prostatic hyperplasia

“…18 The process of apoptosis protects the integrity of the genome by eliminating cells with extensive DNA damage or those undergoing uncontrolled proliferation. 11 For instance, during development, RB knockout mice did not experience uncontrolled cellular growth as expected because apoptotic processes eliminated abnormally cycling cells. 21 Similarly, transfection of the G1 cell cycle regulator Cyclin D1 into rat embryo cells, which also disrupts the RB pathway, resulted in increased apoptosis.…”

“…6 Bax has been recognized as a potent proapoptotic regulator and the intracellular balance of Bax and Bcl-2 described as a 'rheostat' of apoptosis sensitivity in that the ratio of these proteins influences a cell's ability to respond to apoptotic signals. [11][12][13] Both Bax and Bcl-2 are noted to form homo-and heterodimers and this ratio of these dimeric forms propels the cells towards survival or apoptosis. 11 Two investigators have assessed the expression of BAX and Bcl-2 in in vivo models of castrationinduced prostate apoptosis.…”

“…[11][12][13] Both Bax and Bcl-2 are noted to form homo-and heterodimers and this ratio of these dimeric forms propels the cells towards survival or apoptosis. 11 Two investigators have assessed the expression of BAX and Bcl-2 in in vivo models of castrationinduced prostate apoptosis. Perlman et al 14 observed a transient but marked increase in the BAX : Bcl-2 gene expression ratio in prostatic tissue that peaked on the 2nd and 3rd days after castration of adult male rats.…”

Human EHMT2/G9a activates p53 through methylation-independent mechanism

“…p53, known as a "guardian of genome", responses to various forms of cytotoxic stress by preventing the proliferation of genetically damaged cells through the control of their cell cycle and/or apoptosis. p53 executes its stress-response programmes through regulation of expression of its target genes, including p21, GADD45α (cell cycle arrest) 4,5 , PUMA 6 , BAX 7 , NOXA 8 , DR5, p53AIP, PIG3, APAF1 (apoptosis) 5 , BTG2, and PaI1(senescence) 5 . In addition to proteincoding genes p53 also controls a number of micro-RNA and long non-coding genes 28: 1739-1751; Grigoreva T et al, Oncotarget, 2015).…”