Reference SummaryTan M, Cell Rep 2022 Dec 20;41(12):111837
Title |
The Sag-Shoc2 axis regulates conversion of mPanINs to cystic lesions in Kras pancreatic tumor model. |
Authors |
Tan M; Chang Y; Liu X; Li H; Tang Z; Nyati MK; Sun Y |
Journal |
Cell Rep |
Volume |
41 |
Issue |
12 |
Year |
2022 |
Pages |
111837 |
Abstract |
SAG/RBX2 is an E3 ligase, whereas SHOC2 is a RAS-RAF positive regulator. In this study, we address how Sag-Shoc2 crosstalk regulates pancreatic tumorigenesis induced by Kras(G12D). Sag deletion increases the size of pancreas and causes the conversion of murine pancreatic intraepithelial neoplasms (mPanINs) to neoplastic cystic lesions with a mechanism involving Shoc2 accumulation, suggesting that Sag determines the pathological process via targeting Shoc2. Shoc2 deletion significantly inhibits pancreas growth, mPanIN formation, and acinar cell transdifferentiation, indicating that Shoc2 is essential for Kras(G12D)-induced pancreatic tumorigenesis. Likewise, in a primary acinar 3D culture, Sag deletion inhibits acinar-to-ductal transdifferentiation, while Shoc2 deletion significantly reduces the duct-like structures. Mechanistically, SAG is an E3 ligase that targets SHOC2 for degradation to affect both Mapk and mTorc1 pathways. Shoc2 deletion completely rescues the phenotype of neoplastic cystic lesions induced by Sag deletion, indicating physiological relevance of the Sag-Shoc2 crosstalk. Thus, the Sag-Shoc2 axis specifies the pancreatic tumor types induced by Kras(G12D). |
Links |
J:332394 – MGI References 36543126 – National Library of Medicine/PubMed |
| Strain | Model Name | Treatment Agent(s) | Organ Affected | Frequency | Model Details |
|---|---|---|---|---|---|
| C57BL/6-Krastm4Tyj/+ Ptf1atm1.1(cre)Cvw/+ | Pancreas - Acinar cell metaplasia - ductal | Pancreas - Acinar cell |
observed |
||
| SHN | Pancreas - Acinar cell metaplasia - ductal | Pancreas - Acinar cell |
observed |
||
| C57BL/6-Krastm4Tyj/+ Ptf1atm1.1(cre)Cvw/+ Shoc2tm1.1Mhan | Pancreas - Acinar cell metaplasia - ductal | Pancreas - Acinar cell |
observed |
||
| C57BL/6-Krastm4Tyj/+ Ptf1atm1.1(cre)Cvw/+ | Pancreas adenocarcinoma - ductal | Pancreas |
observed |
||
| C57BL/6-Krastm4Tyj/+ Ptf1atm1.1(cre)Cvw/+ Rnf7tm1.1Ysun | Pancreas adenocarcinoma - ductal | Pancreas |
observed |
||
| C57BL/6-Krastm4Tyj/+ Ptf1atm1.1(cre)Cvw/+ Shoc2tm1.1Mhan | Pancreas adenocarcinoma - ductal | Pancreas |
0 |
||
| C57BL/6-Krastm4Tyj/+ Ptf1atm1.1(cre)Cvw/+ Shoc2tm1.1Mhan Rnf7tm1.1Ysun | Pancreas adenocarcinoma - ductal | Pancreas |
0 |
||
| C57BL/6-Krastm4Tyj/+ Ptf1atm1.1(cre)Cvw/+ Rnf7tm1.1Ysun | Pancreas cyst | Pancreas |
observed |
||
| C57BL/6-Krastm4Tyj/+ Ptf1atm1.1(cre)Cvw/+ Rnf7tm1.1Ysun | Pancreas dysplasia - low grade | Pancreas |
observed |
||
| C57BL/6-Krastm4Tyj/+ Ptf1atm1.1(cre)Cvw/+ Rnf7tm1.1Ysun | Pancreas hyperplasia | Pancreas |
observed |
||
| C57BL/6-Krastm4Tyj/+ Ptf1atm1.1(cre)Cvw/+ | Pancreas hyperplasia | Pancreas |
observed |
||
| C57BL/6-Krastm4Tyj/+ Ptf1atm1.1(cre)Cvw/+ Shoc2tm1.1Mhan | Pancreas hyperplasia | Pancreas |
0 |
||
| C57BL/6-Krastm4Tyj/+ Ptf1atm1.1(cre)Cvw/+ Rnf7tm1.1Ysun | Pancreas lesion - cystic | Pancreas |
observed - 100 |
||
| C57BL/6-Krastm4Tyj/+ Ptf1atm1.1(cre)Cvw/+ | Pancreas lesion - cystic | Pancreas |
0 - 10 |
||
| C57BL/6-Krastm4Tyj/+ Ptf1atm1.1(cre)Cvw/+ Shoc2tm1.1Mhan | Pancreas lesion - cystic | Pancreas |
0 |
||
| C57BL/6-Krastm4Tyj/+ Ptf1atm1.1(cre)Cvw/+ Shoc2tm1.1Mhan Rnf7tm1.1Ysun | Pancreas lesion - cystic | Pancreas |
0 |
||
| C57BL/6-Krastm4Tyj/+ Ptf1atm1.1(cre)Cvw/+ Rnf7tm1.1Ysun | Pancreas lesion - neoplastic | Pancreas |
57 - 100 |
||
| C57BL/6-Krastm4Tyj/+ Ptf1atm1.1(cre)Cvw/+ Rnf7tm1.1Ysun | Pancreas neoplasia - mucinous - papillary - intraductal | Pancreas |
observed |
||
| C57BL/6-Krastm4Tyj/+ Ptf1atm1.1(cre)Cvw/+ Rnf7tm1.1Ysun | Pancreas neoplasm - cystic - mucinous | Pancreas |
0 |
||
| C57BL/6-Krastm4Tyj/+ Ptf1atm1.1(cre)Cvw/+ | Pancreas pancreatic intraepithelial neoplasia 1 (PanIN1) | Pancreas |
observed |
||
| SHN | Pancreas pancreatic intraepithelial neoplasia 1 (PanIN1) | Pancreas |
observed |
||
| STOCK Tg(Wap-HRAS)69Lln Chr YSJL | Pancreas pancreatic intraepithelial neoplasia 1 (PanIN1) | Pancreas |
observed |
||
| C57BL/6-Krastm4Tyj/+ Ptf1atm1.1(cre)Cvw/+ Rnf7tm1.1Ysun | Pancreas pancreatic intraepithelial neoplasia 1 (PanIN1) | Pancreas |
observed |
||
| C57BL/6-Krastm4Tyj/+ Ptf1atm1.1(cre)Cvw/+ Shoc2tm1.1Mhan | Pancreas pancreatic intraepithelial neoplasia 1 (PanIN1) | Pancreas |
observed |
||
| C57BL/6-Krastm4Tyj/+ Ptf1atm1.1(cre)Cvw/+ Shoc2tm1.1Mhan Rnf7tm1.1Ysun | Pancreas pancreatic intraepithelial neoplasia 1 (PanIN1) | Pancreas |
observed |
||
| C57BL/6-Krastm4Tyj/+ Ptf1atm1.1(cre)Cvw/+ | Pancreas pancreatic intraepithelial neoplasia 2 (PanIN2) | Pancreas |
observed |
||
| C57BL/6-Krastm4Tyj/+ Ptf1atm1.1(cre)Cvw/+ Rnf7tm1.1Ysun | Pancreas pancreatic intraepithelial neoplasia 2 (PanIN2) | Pancreas |
observed |
||
| C57BL/6-Krastm4Tyj/+ Ptf1atm1.1(cre)Cvw/+ | Pancreas pancreatic intraepithelial neoplasia 2 (PanIN2) | PNS - Schwann cell |
observed |
||
| C57BL/6-Krastm4Tyj/+ Ptf1atm1.1(cre)Cvw/+ Shoc2tm1.1Mhan | Pancreas pancreatic intraepithelial neoplasia 2 (PanIN2) | PNS - Schwann cell |
observed |
||
| C57BL/6-Krastm4Tyj/+ Ptf1atm1.1(cre)Cvw/+ Shoc2tm1.1Mhan | Pancreas pancreatic intraepithelial neoplasia 2 (PanIN2) | Pancreas |
observed |
||
| C57BL/6-Krastm4Tyj/+ Ptf1atm1.1(cre)Cvw/+ Shoc2tm1.1Mhan Rnf7tm1.1Ysun | Pancreas pancreatic intraepithelial neoplasia 2 (PanIN2) | Pancreas |
observed |
||
| C57BL/6-Krastm4Tyj/+ Ptf1atm1.1(cre)Cvw/+ | Pancreas pancreatic intraepithelial neoplasia 3 (PanIN3) | Pancreas |
observed |
||
| C57BL/6-Krastm4Tyj/+ Ptf1atm1.1(cre)Cvw/+ Rnf7tm1.1Ysun | Pancreas pancreatic intraepithelial neoplasia 3 (PanIN3) | Pancreas |
observed |
||
| C57BL/6-Krastm4Tyj/+ Ptf1atm1.1(cre)Cvw/+ Shoc2tm1.1Mhan | Pancreas pancreatic intraepithelial neoplasia 3 (PanIN3) | Pancreas |
0 - observed |
||
| C57BL/6-Krastm4Tyj/+ Ptf1atm1.1(cre)Cvw/+ Shoc2tm1.1Mhan Rnf7tm1.1Ysun | Pancreas pancreatic intraepithelial neoplasia 3 (PanIN3) | Pancreas |
0 |