Dataset Information

DHX33 Interacts with AP-2? To Regulate Bcl-2 Gene Expression and Promote Cancer Cell Survival.

ABSTRACT: The RNA helicase DHX33 has been found to be overexpressed in human cancers, where it promotes cancer development. Previous reports have shown that DHX33 deficiency caused cancer cell apoptosis, but the underlying mechanism remains unknown. In this study, we discovered that DHX33 regulates Bcl-2 family protein expression. In multiple human cancer cell lines, DHX33 was found to stimulate the transcription of Bcl-2 Mechanistically, we found that DHX33 interacts with the AP-2? transcription factor and acts as a coactivator to stimulate Bcl-2 gene transcription. DHX33 deficiency abolished the loading of AP-2? onto the promoter of Bcl-2 and thereby reduced the recruitment of active RNA polymerase II during transcription initiation. Acute knockdown of DHX33 in multiple human cancer cells caused decreased Bcl-2 protein level, which ultimately triggered mitochondrion-mediated cellular apoptosis. In addition, we found that normal human lung and mammary epithelial cells were less sensitive to acute DHX33 knockdown, implying that cancer cells are uniquely responsive to DHX33 reduction. These data support the notion that disruption of DHX33 function could be an important application for cancer therapy.

SUBMITTER: Wang J

PROVIDER: S-EPMC6692123 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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DHX33 Interacts with AP-2β To Regulate <i>Bcl-2</i> Gene Expression and Promote Cancer Cell Survival.

Wang Jiuling J Feng Weimin W Yuan Zhen Z Weber Jason D JD Zhang Yandong Y

Molecular and cellular biology 20190812 17

The RNA helicase DHX33 has been found to be overexpressed in human cancers, where it promotes cancer development. Previous reports have shown that DHX33 deficiency caused cancer cell apoptosis, but the underlying mechanism remains unknown. In this study, we discovered that DHX33 regulates Bcl-2 family protein expression. In multiple human cancer cell lines, DHX33 was found to stimulate the transcription of <i>Bcl-2</i> Mechanistically, we found that DHX33 interacts with the AP-2β transcription f ...[more]

PMID: 31182639

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Project description:The molecular mechanism regulating sleep largely remains to be elucidated. In humans, families that carry mutations in TFAP2B, which encodes the transcription factor AP-2β, self-reported sleep abnormalities such as short-sleep and parasomnia. Notably, AP-2 transcription factors play essential roles in sleep regulation in the nematode Caenorhabditis elegans and the fruit fly Drosophila melanogaster Thus, AP-2 transcription factors might have a conserved role in sleep regulation across the animal phyla. However, direct evidence supporting the involvement of TFAP2B in mammalian sleep was lacking. In this study, by using the CRISPR/Cas9 technology, we generated two Tfap2b mutant mouse strains, Tfap2bK144 and Tfap2bK145 , each harboring a single-nucleotide mutation within the introns of Tfap2b mimicking the mutations in two human kindreds that self-reported sleep abnormalities. The effects of these mutations were compared with those of a Tfap2b knockout allele (Tfap2b-). The protein expression level of TFAP2B in the embryonic brain was reduced to about half in Tfap2b+/- mice and was further reduced in Tfap2b-/- mice. By contrast, the protein expression level was normal in Tfap2bK145/+ mice but was reduced in Tfap2bK145/K145 mice to a similar extent as Tfap2b-/- mice. Tfap2bK144/+ and Tfap2bK144/K144 showed normal protein expression levels. Tfap2b+/- female mice showed increased wakefulness time and decreased nonrapid eye movement sleep (NREMS) time. By contrast, Tfap2bK145/+ female mice showed an apparently normal amount of sleep but instead exhibited fragmented NREMS, whereas Tfap2bK144/+ male mice showed reduced NREMS time specifically in the dark phase. Finally, in the adult brain, Tfap2b-LacZ expression was detected in the superior colliculus, locus coeruleus, cerebellum, and the nucleus of solitary tract. These findings provide direct evidence that TFAP2B influences NREMS amounts in mice and also show that different mutations in Tfap2b can lead to diverse effects on sleep architecture.

Dataset Information

DHX33 Interacts with AP-2? To Regulate Bcl-2 Gene Expression and Promote Cancer Cell Survival.

Publications

DHX33 Interacts with AP-2β To Regulate <i>Bcl-2</i> Gene Expression and Promote Cancer Cell Survival.

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