| First Author | Ling J | Year | 2012 |
| Journal | Cancer Cell | Volume | 21 |
| Issue | 1 | Pages | 105-20 |
| PubMed ID | 22264792 | Mgi Jnum | J:180278 |
| Mgi Id | MGI:5306053 | Doi | 10.1016/j.ccr.2011.12.006 |
| Citation | Ling J, et al. (2012) Kras(G12D)-Induced IKK2/beta/NF-kappaB Activation by IL-1alpha and p62 Feedforward Loops Is Required for Development of Pancreatic Ductal Adenocarcinoma. Cancer Cell 21(1):105-20 |
| abstractText | Constitutive Kras and NF-kappaB activation is identified as signature alterations in pancreatic ductal adenocarcinoma (PDAC). However, how NF-kappaB is activated in PDAC is not yet understood. Here, we report that pancreas-targeted IKK2/beta inactivation inhibited NF-kappaB activation and PDAC development in Kras(G12D) and Kras(G12D);Ink4a/Arf(F/F) mice, demonstrating a mechanistic link between IKK2/beta and Kras(G12D) in PDAC inception. Our findings reveal that Kras(G12D)-activated AP-1 induces IL-1alpha, which, in turn, activates NF-kappaB and its target genes IL-1alpha and p62, to initiate IL-1alpha/p62 feedforward loops for inducing and sustaining NF-kappaB activity. Furthermore, IL-1alpha overexpression correlates with Kras mutation, NF-kappaB activity, and poor survival in PDAC patients. Therefore, our findings demonstrate the mechanism by which IKK2/beta/NF-kappaB is activated by Kras(G12D) through dual feedforward loops of IL-1alpha/p62. |
