Normal proliferation and tumorigenesis but impaired pancreatic function in mice lacking the cell cycle regulator sei1

Area of Science:

• Cell Biology
• Molecular Biology
• Endocrinology

Background:

• Sei1 acts as a positive regulator of cell proliferation by promoting Cdk4-cyclin D complex assembly and enhancing E2f1 transcriptional activity.
• Overexpression of Sei1 in human cancers suggests a potential oncogenic role.
• Sei1's role in normal physiological processes, particularly in the pancreas, remained largely uncharacterized.

Purpose of the Study:

• To investigate the physiological role of Sei1 using a gene-deficient mouse model.
• To determine if Sei1 deficiency impacts proliferation, neoplastic transformation, or cancer susceptibility.
• To elucidate the specific function of Sei1 in pancreatic beta-cells and its relation to cell cycle regulation.

Main Methods:

• Generation and characterization of Sei1-null mice.
• Analysis of fibroblast proliferation and neoplastic transformation.
• Assessment of Cdk4 complexes and E2f activity in Sei1-deficient cells.
• Evaluation of Sei1-null mouse viability, lifespan, pathology, and cancer susceptibility.
• Detailed examination of pancreatic islet morphology, beta-cell function, insulin secretion, and glucose tolerance in Sei1-null mice.

Main Results:

• Sei1-null fibroblasts exhibited normal proliferation and resistance to neoplastic transformation.
• Sei1-null mice were viable, showed no overt pathologies, and had normal lifespan and cancer susceptibility.
• Sei1-null mice displayed reduced islet number, decreased beta-cell area, impaired insulin secretion, and glucose intolerance.
• These pancreatic defects in Sei1-null mice were linked to the nuclear accumulation of p21(Cip1) and p27(Kip1) in islet cells.

Conclusions:

• Sei1 is not essential for general cell proliferation or cancer development.
• Sei1 plays a critical and specific role in the function and maintenance of pancreatic beta-cells.
• The findings establish a functional link between Sei1 and core cell cycle regulators within the pancreatic context, impacting glucose homeostasis.