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Expression and modulation of p42/p44 MAPKs and cell cycle regulatory proteins in rat pancreas regeneration
J Morisset1, J C Aliaga, E L Calvo
1Service de gastro-entérologie, Département de Médecine, Faculté de Médecine, Université de Sherbrooke, Sherbrooke, Quebec, Canada J1H 5N4. jmori7@courrier.usherb.ca
Abstract:
Pancreatic growth occurs after CCK, CCK-induced pancreatitis, and pancreatectomy; the mechanisms involved remain unknown. This study evaluates mitogen-activated protein kinase (MAPK) activation and expression of cell cycle regulatory proteins after pancreatectomy to understand the cellular and molecular mechanisms involved in pancreas regeneration. Rats were killed 1-12 days after pancreatectomy, and p42/p44 MAPK activation, expression of the cyclins D and E, cyclin-dependent kinase (Cdk)-2 activity, retinoblastoma protein (pRb) hyperphosphorylation, and expression of the cyclin kinase inhibitors p15, p21, and p27 were examined. Pancreatic remnants exhibited sustained p42/p44 MAPK activation within 8 h. Cyclins D1 and E showed maximal expression after 2 and 6 days, coinciding with maximal hyperphosphorylation of pRb and Cdk2 activity. The expression of p15 vanished after 12 h, p27 disappeared gradually, and p21 increased early. The p27 complexed with Cdk2 dissociated after 2 days, whereas p21 associated in a reverse fashion. In conclusion, sustained activation of p42/p44 MAPKs and Cdk2 along with overexpression of cyclins D1 and E and reduction of p15 and p27 cyclin inhibitors occurred early after pancreatectomy and are active factors involved in signaling that leads to pancreas regeneration.
Insights
Pancreas regeneration after surgery involves sustained activation of mitogen-activated protein kinase (MAPK) and cyclin-dependent kinase 2 (Cdk2). These pathways promote cell cycle progression by regulating cyclin and cyclin kinase inhibitor expression.
Area of Science:
- Cell Biology
- Molecular Biology
- Regenerative Medicine
Background:
- Pancreatic growth is observed following cholecystokinin (CCK) stimulation, pancreatitis, and pancreatectomy.
- The precise molecular mechanisms driving pancreas regeneration remain largely unknown.
Purpose of the Study:
- To investigate mitogen-activated protein kinase (MAPK) activation and cell cycle regulatory protein expression during pancreas regeneration after pancreatectomy.
- To elucidate the cellular and molecular signaling pathways involved in pancreatic regeneration.
Main Methods:
- Rats underwent pancreatectomy, with samples collected 1-12 days post-surgery.
- Assessed p42/p44 MAPK activation, cyclin D and E expression, Cdk2 activity, retinoblastoma protein (pRb) hyperphosphorylation, and expression of cyclin kinase inhibitors (p15, p21, p27).
Main Results:
- Sustained p42/p44 MAPK activation was observed within 8 hours post-pancreatectomy.
- Maximal expression of cyclins D1 and E, pRb hyperphosphorylation, and Cdk2 activity occurred at 2 and 6 days.
- Dynamic changes in cyclin kinase inhibitors: p15 expression vanished by 12 hours, p27 decreased gradually, and p21 expression increased early.
Conclusions:
- Sustained activation of p42/p44 MAPKs and Cdk2 are key early events in pancreas regeneration.
- Overexpression of cyclins D1 and E, coupled with reduced p15 and p27, actively contributes to the signaling cascade driving pancreatic regeneration.