p53 Suppresses the Activation of the Bcl-2 Promoter by the Brn-3a POU Family Transcription Factor

Abstract

The Brn-3a POU family transcription factor has been shown to strongly activate expression of the Bcl-2 protooncogene and thereby protect neuronal cells from programmed cell death (apoptosis). This activation of the Bcl-2 promoter by Brn-3a is strongly inhibited by the p53 anti-oncogene protein. This inhibitory effect of p53 on Brn-3a-mediated transactivation is observed with nonoverlapping gene fragments containing either the Bcl-2 p1 or p2 promoters but is not observed with other Brn-3a-activated promoters such as in the gene encoding ␣-internexin or with an isolated Brn-3a binding site from the Bcl-2 promoter linked to a heterologous promoter. In contrast, p53 mutants, which are incapable of binding to DNA, do not affect Brn-3a-mediated activation of the Bcl-2 p1 and p2 promoters. Moreover, Brn-3a and p53 have been shown to bind to adjacent sites in the p2 promoter and to directly interact with one another, both in vitro and in vivo, with this interaction being mediated by the POU domain of Brn-3a and the DNA binding domain of p53. The significance of these effects is discussed in terms of the antagonistic effects of Bcl-2 and p53 on the rate of apoptosis and the overexpression of Brn-3a in specific tumor cell types.The rate of apoptosis (programmed cell death) is controlled by the balance between proteins that activate processes resulting in such death and other proteins that act to inhibit these processes. Thus, for example, the Bcl-2 proto-oncogene was originally identified on the basis of its activation by chromosomal translocation in non-Hodgkin B cell lymphomas (1) and was subsequently shown to protect a wide variety of different cell types from programmed cell death or apoptosis (for review see Ref.2). Conversely, the p53 anti-oncogene protein, as well as inhibiting cellular proliferation, can also stimulate programmed cell death (for review see Ref.3).It is clear therefore that Bcl-2 and p53 represent proteins with opposite effects on the rate of apoptosis. Moreover, it appears that Bcl-2 can specifically inhibit p53-dependent apoptosis. Thus, although overexpression of p53 can induce apoptosis in different cell types, this is prevented by overexpression of Bcl-2 (4, 5). In this regard, it is of interest that high levels of p53 are associated with low levels of Bcl-2 and vice versa, both during normal rat development (6) and in different types of tumors (7-9).These findings suggest therefore that as well as being functionally antagonistic to one another, p53 and Bcl-2 may also be interlinked in terms of the processes regulating their expression. This possibility is supported by the finding that artificial overexpression of p53 in a murine leukemia cell line results in reduced Bcl-2 expression (10). Similarly, Bcl-2 levels are elevated in several tissues of knockout mice lacking functional p53 (10, 11). Evidently, these results raised the possibility that the p53 transcription factor may have an inhibitory effect on Bcl-2 gene transcription. In agreement with this it has been shown that p53 can inhibit ...

Stimulation-induced gene expression in Ramos B-cells

“…21 Homeobox/POU domain protein 3A (BRN-3A) (AA428196) is expressed at 124 h. This protein was previously shown to be expressed in activated Jurkat T cells 22 where it activates Bcl-2 proto-oncogene expression, thereby protecting cells from apoptosis. 23 IRX-2a (R46202), which participates in epithelial cell differentiation, 24 is expressed late in the time course.…”

The miR-34 family in cancer and apoptosis

“…This dual regulation allows an accelerated transition to the offstate. This may be the case for Bcl-2, because its transcription is directly repressed by p53, as discussed above, 14 and its 3 0 -UTR is targeted by miR-34a. 35 …”

“…13 For example, the survival factor, Bcl-2, is transcriptionally repressed by p53 through steric interference with DNA binding of the POU4F1 transcription factor at the Bcl-2 promoter. 14 The discovery of microRNAs (miRNAs) suggested that the p53-mediated induction of miRNAs might contribute to the downregulation of proteins observed after p53 activation. miRNAs form a class of endogenously expressed, small noncoding RNAs that mediate post-transcriptional regulation of gene expression (reviewed in Ref.…”

Brn-3a/POU4F1 interacts with and differentially affects p73-mediated transcription

“…The ND7 cell line, which is derived by fusing non-dividing rat dorsal root ganglion cells with the C1300 mouse neuroblastoma cell line was previously described, 22 and the p53 null human osteogenic sarcoma cell line SAOS-2 cell line was obtained from ATCC (USA). For culture, ND7 cells were grown in full growth media (1 Â L15 with 10% fetal calf serum (FCS)) supplemented with 0.3% glucose, 0.37% sodium bicarbonate and 0.2 mM L-glutamine.…”

“…For example, ASPP1/2 proteins interact with p53 and TAp73 proteins to enhance transcription of pro-apoptotic genes 19 whereas Brn-3a interacts with p53 but differentially regulates its ability to transactivate its target genes. [20][21][22] p73 KO mice display varying degrees of abnormal neurological development in different parts of the nervous system, which results in an increased death rate within weeks after birth. 23 This phenotype seems to be mainly related to the absence of DNp73, thus demonstrating specific functions for p73 isoforms in specific neuronal cells.…”