Wan, Ledong, Lin, Kuan-Ting, Rahman, Mohammad Alinoor, Wang, Zhikai, Jensen, Mads, Park, Youngkyu, Tuveson, David, Krainer, Adrian (2021) Loss of KRAS G12D feedback regulation involving splicing factor SRSF1 accelerates pancreatic cancer. bioRxiv. (Submitted)
Abstract
The gene encoding KRAS GTPase is recurrently mutated in pancreatic ductal adenocarcinoma (PDAC), triggering the formation of precursor lesions, i.e., acinar-to-ductal metaplasia (ADM) and pancreatic intraepithelial neoplasia (PanIN). However, the majority of pancreatic cells from KC (LSL-KrasG12D/+; Pdx-1-Cre) mice expressing the KrasG12D mutation remain morphologically normal for a long time, suggesting the existence of compensatory feedback mechanisms that buffer aberrant KrasG12D signaling, and that additional steps are required for disrupting cell homeostasis and promoting transformation. Here we report a feedback mechanism in which the ubiquitously expressed splicing factor SRSF1—which is associated with cell transformation in multiple cell types—is downregulated in the majority of morphologically normal pancreas cells with the KrasG12D mutation. Conversely, increasing SRSF1 expression disrupts cell homeostasis by activating MAPK signaling, in part by regulating alternative splicing and mRNA stability of interleukin 1 receptor type 1 (Il1r1). This disruption in homeostasis in turn accelerates KrasG12D-mediated PDAC initiation and progression. Our results demonstrate the involvement of SRSF1 in the pancreatic-cell homeostatic response against the KrasG12D mutation, dysregulation of which facilitates PDAC initiation.
| Item Type: | Paper |
|---|---|
| Subjects: | bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types > KRAS diseases & disorders > cancer > cancer types > pancreatic cancer |
| CSHL Authors: | |
| Communities: | CSHL labs > Fearon lab CSHL labs > Krainer lab CSHL labs > Tuveson lab |
| SWORD Depositor: | CSHL Elements |
| Depositing User: | CSHL Elements |
| Date: | 2021 |
| Date Deposited: | 03 Oct 2023 19:53 |
| Last Modified: | 23 May 2024 13:03 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/41112 |
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