Dataset Information

Conversion of a Non-Cancer-Selective Promoter into a Cancer-Selective Promoter.

ABSTRACT: Progression-elevated gene-3 (PEG-3) and rat growth arrest and DNA damage-inducible gene-34 (GADD34) display significant sequence homology with regulation predominantly transcriptional. The rat full-length (FL) and minimal (min) PEG-3 promoter display cancer-selective expression in rodent and human tumors, allowing for cancer-directed regulation of transgenes, viral replication and in vivo imaging of tumors and metastases in animals, whereas the FL- and min-GADD34-Prom lack cancer specificity. Min-PEG-Prom and min-GADD34-Prom have identical sequences except for two single-point mutation differences (at -260 bp and +159 bp). Engineering double mutations in the min-GADD34-Prom produce the GAPE-Prom. Changing one base pair (+159) or both point mutations in the min-GADD34-Prom, but not the FL-GADD34-Prom, results in cancer-selective transgene expression in diverse cancer cells (including prostate, breast, pancreatic and neuroblastoma) vs. normal counterparts. Additionally, we identified a GATA2 transcription factor binding site, promoting cancer specificity when both min-PEG-Prom mutations are present in the GAPE-Prom. Taken together, introducing specific point mutations in a rat min-GADD34-Prom converts this non-cancer-specific promoter into a cancer-selective promoter, and the addition of GATA2 with existing AP1 and PEA3 transcription factors enhances further cancer-selective activity of the GAPE-Prom. The GAPE-Prom provides a genetic tool to specifically regulate transgene expression in cancer cells.

SUBMITTER: Bhoopathi P

PROVIDER: S-EPMC8946048 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature

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Publications

Conversion of a Non-Cancer-Selective Promoter into a Cancer-Selective Promoter.

Bhoopathi Praveen P Pradhan Anjan K AK Kumar Amit A Maji Santanu S Mannangatti Padmanabhan P Deng Xiaoyan X Bandyopadhyay Dipankar D Sarkar Devanand D Wang Xiang-Yang XY Landry Joseph W JW Das Swadesh K SK Emdad Luni L Fisher Paul B PB

Cancers 20220315 6

Progression-elevated gene-3 (PEG-3) and rat growth arrest and DNA damage-inducible gene-34 (GADD34) display significant sequence homology with regulation predominantly transcriptional. The rat full-length (FL) and minimal (min) PEG-3 promoter display cancer-selective expression in rodent and human tumors, allowing for cancer-directed regulation of transgenes, viral replication and in vivo imaging of tumors and metastases in animals, whereas the FL- and min-GADD34-Prom lack cancer specificity. Mi ...[more]

PMID: 35326649

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Project description:The prominence of positive selection, in which beneficial mutations are favored by natural selection and rapidly increase in frequency, is a subject of intense debate. Positive selection can result in selective sweeps, in which the haplotype(s) bearing the adaptive allele "sweep" through the population, thereby removing much of the genetic diversity from the region surrounding the target of selection. Two models of selective sweeps have been proposed: classical sweeps, or "hard sweeps", in which a single copy of the adaptive allele sweeps to fixation, and "soft sweeps", in which multiple distinct copies of the adaptive allele leave descendants after the sweep. Soft sweeps can be the outcome of recurrent mutation to the adaptive allele, or the presence of standing genetic variation consisting of multiple copies of the adaptive allele prior to the onset of selection. Importantly, soft sweeps will be common when populations can rapidly adapt to novel selective pressures, either because of a high mutation rate or because adaptive alleles are already present. The prevalence of soft sweeps is especially controversial, and it has been noted that selection on standing variation or recurrent mutations may not always produce soft sweeps. Here, we show that the inverse is true: selection on single-origin de novo mutations may often result in an outcome that is indistinguishable from a soft sweep. This is made possible by allelic gene conversion, which "softens" hard sweeps by copying the adaptive allele onto multiple genetic backgrounds, a process we refer to as a "pseudo-soft" sweep. We carried out a simulation study examining the impact of gene conversion on sweeps from a single de novo variant in models of human, Drosophila, and Arabidopsis populations. The fraction of simulations in which gene conversion had produced multiple haplotypes with the adaptive allele upon fixation was appreciable. Indeed, under realistic demographic histories and gene conversion rates, even if selection always acts on a single-origin mutation, sweeps involving multiple haplotypes are more likely than hard sweeps in large populations, especially when selection is not extremely strong. Thus, even when the mutation rate is low or there is no standing variation, hard sweeps are expected to be the exception rather than the rule in large populations. These results also imply that the presence of signatures of soft sweeps does not necessarily mean that adaptation has been especially rapid or is not mutation limited.

Dataset Information

Conversion of a Non-Cancer-Selective Promoter into a Cancer-Selective Promoter.

Publications

Conversion of a Non-Cancer-Selective Promoter into a Cancer-Selective Promoter.

Similar Datasets

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