| First Author | Principe DR | Year | 2017 |
| Journal | Oncogene | Volume | 36 |
| Issue | 30 | Pages | 4336-4348 |
| PubMed ID | 28368414 | Mgi Jnum | J:243603 |
| Mgi Id | MGI:5909182 | Doi | 10.1038/onc.2016.500 |
| Citation | Principe DR, et al. (2017) TGFbeta engages MEK/ERK to differentially regulate benign and malignant pancreas cell function. Oncogene 36(30):4336-4348 |
| abstractText | While TGFbeta signals are anti-proliferative in benign and well-differentiated pancreatic cells, TGFbeta appears to promote the progression of advanced cancers. To better understand dysregulation of the TGFbeta pathway, we first generated mouse models of neoplastic disease with TGFbeta receptor deficiencies. These models displayed reduced levels of pERK irrespective of KRAS mutation. Furthermore, exogenous TGFbeta led to rapid and sustained TGFBR1-dependent ERK phosphorylation in benign pancreatic duct cells. Similar to results that our group has published in colon cancer cells, inhibition of ERK phosphorylation in duct cells mitigated TGFbeta-induced upregulation of growth suppressive pSMAD2 and p21, prevented downregulation of the pro-growth signal CDK2 and ablated TGFbeta-induced EMT. These observations suggest that ERK is a key factor in growth suppressive TGFbeta signals, yet may also contribute to detrimental TGFbeta signaling such as EMT. In neoplastic PanIN cells, pERK was not necessary for either TGFbeta-induced pSMAD2 phosphorylation or CDK2 repression, but was required for upregulation of p21 and EMT indicating a partial divergence between TGFbeta and MEK/ERK in early carcinogenesis. In cancer cells, pERK had no effect on TGFbeta-induced upregulation of pSMAD2 and p21, suggesting the two pathways have completely diverged with respect to the cell cycle. Furthermore, inhibition of pERK both reduced levels of CDK2 and prevented EMT independent of exogenous TGFbeta, consistent with most observations identifying pERK as a tumor promoter. Combined, these data suggest that during carcinogenesis pERK initially facilitates and later antagonizes TGFbeta-mediated cell cycle arrest, yet remains critical for the pathological, EMT-inducing arm of TGFbeta signaling. |
