Abstract 4441: Functional and clinical implications of an INDEL within the HuR regulatory region of the mitotic kinase inhibitor WEE1
| Autor: | Avinoam Nevler, Alexis Norris-Kirby, Fernando F. Blanco, Jordan M. Winter, Samantha Z. Brown, Henry T. Thomsett, Jonathan R. Brody, Joseph A. Cozzitorto, Charles J. Yeo, Shruti Lal, James R. Eshleman, Mahsa Zarei |
|---|---|
| Rok vydání: | 2018 |
| Předmět: | |
| Zdroj: | Cancer Research. 78:4441-4441 |
| ISSN: | 1538-7445 0008-5472 |
| DOI: | 10.1158/1538-7445.am2018-4441 |
| Popis: | The RNA-binding protein Human Antigen R (HuR) is upregulated in pancreatic ductal adenocarcinoma (PDA), where it promotes tumorigenesis via its mRNA pro-survival targets. PDA cells exposed to DNA damage upregulate the mitotic inhibitor kinase, WEE1, in a HuR-dependent manner to induce cell cycle arrest and facilitate drug-resistance (1). Herein, we further evaluate a 56 base-pair (bp) region within WEE1's 3'UTR (labeled WEE1.3UTR) where HuR binds and stabilizes expression. Within this regulatory site, we observed that a 10-thymidine (T) track contains frequent polymorphisms (mean allele frequency 8.67%) of thymidine insertions (i.e, an INDEL). Using a combined approach of Sanger sequencing and a more sensitive capillary-electrophoresis (CE) assay, we screened this region in various cancer cell lines and patient samples. Results revealed three distinct alleles between individual cohorts: the wild-type (10-T, 56 bps), a 1-T insertion (11-T, 57 bps), and a 2-T insertion (12-T, 58 bps). Luciferase reporter constructs were subcloned with the HuR regulatory region embedded in the WEE1.3'UTR. In response to stress, constructs with the wild-type allele reported a higher level of expression compared to the 11-T and 12-T alleles (p Reference: 1. Lal et al., Cancer Res 2014;74(4):1128-40. Citation Format: Samantha Z. Brown, Avinoam Nevler, Henry T. Thomsett, Shruti Lal, Mahsa Zarei, Fernando Blanco, Joseph A. Cozzitorto, Alexis L. Norris-Kirby, Charles J. Yeo, Jordan M. Winter, James R. Eshleman, Jonathan R. Brody. Functional and clinical implications of an INDEL within the HuR regulatory region of the mitotic kinase inhibitor WEE1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4441. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|