BTG4 is A Novel p53 Target Gene That Inhibits Cell Growth and Induces Apoptosis

Abstract

BTG4 is the last cloned and poorly studied member of BTG/Tob family. Studies have suggested that BTG4 is critical for the degradation of maternal mRNAs in mice during the process of maternal-to-zygotic transition, and downregulated in cancers, such as gastric cancer. However, the regulatory mechanism of BTG4 and its function in cancers remain elusive. In this study, we have for the first time identified the promoter region of the human BTG4 gene. Serial luciferase reporter assay demonstrated that the core promoter of BTG4 is mainly located within the 388 bp region near its transcription initiation site. Transcription factor binding site analysis revealed that the BTG4 promoter contains binding sites for canonical transcription factors, such as Sp1, whereas its first intron contains two overlapped consensus p53 binding sites. However, overexpression of Sp1 has negligible effects on BTG4 promoter activity, and site-directed mutagenesis assay further suggested that Sp1 is not a critical transcription factor for the transcriptional regulation of BTG4. Of note, luciferase assay revealed that one of the intronic p53 binding sites is highly responsive to p53. Both exogenous p53 overexpression and adriamycin-mediated endogenous p53 activation result in the transcriptional upregulation of BTG4. In addition, BTG4 is downregulated in lung and colorectal cancers, and overexpression of BTG4 inhibits cell growth and induces apoptosis in cancer cells. Taken together, our results strongly suggest that BTG4 is a novel p53-regulated gene and probably functions as a tumor suppressor in lung and colorectal cancers.

Isoforms of the p53 Family and Gastric Cancer: A Ménage à Trois for an Unfinished Affair

“…Similarly, p53 can directly induce the expression of miR-508-5p in GC cells, which targets ABCB1 mRNA to favor the response to therapy [ 198 ]. However, there are also more interesting examples, such as the p53 target gene BGT4 that is repressed through promoter methylation (66%), and the restoration of its expression using 5-Aza-DCT induces cell death and reduces tumor growth [ 212 , 213 ]. Another example is the mutations in the p53 target and pro-cell death receptor DR5 that are exclusive of TP53 mutations [ 214 ].…”

The Role of Long Non-Coding RNAs in Intracranial Aneurysms and Subarachnoid Hemorrhage

“…Neuronal apoptosis usually occurs in EBI after SAH [40]. The p53 protein and neural growth factor (NGF) are important factors in many cellular processes, including cell apoptosis [41]. The p53 and NGF have been shown to be orchestrating proteins in the apoptotic pathways following a SAH [41,42].…”

“…The p53 protein and neural growth factor (NGF) are important factors in many cellular processes, including cell apoptosis [41]. The p53 and NGF have been shown to be orchestrating proteins in the apoptotic pathways following a SAH [41,42]. LncRNAs have been shown to regulate p53 and NGF by affecting p53 and NGF mRNA stability and affecting transcription of their target genes.…”

Auto-antibodies against apolipoprotein A-1 block cancer cells proliferation and induce apoptosis

“…All the genes known as inhibitors of cell proliferation but one (CAMKI) were up-regulated. Several of them are direct transcriptional targets of p53: 14.3.3 sigma, GADD45A, B, G, CDKN1C, CDKL2, PLK2, BGT4, PIG3 [27][28][29]. The 14.3.3 sigma, GADD45 alpha and CDKN1C proteins are inhibitors of CDK1, the serine/threonine protein kinase that forms active complex with cyclin B1 and controls the G2/M transition.…”