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Cell cycle regulators during human atrial development
1Department of Obstetrics and Gynecology, Chonbuk National University Medical School, Chonju, Korea.
Objectives:
The molecular mechanisms that regulate cardiomyocyte cell cycle and terminal differentiation in humans remain largely unknown. To determine which cyclins, cyclin dependent kinases (CDKs) and cyclin kinase inhibitors (CKIs) are important for cardiomyocyte proliferation, we have examined protein levels of cyclins, CDKs and CKIs during normal atrial development in humans.
Methods:
Atrial tissues were obtained in the fetus from inevitable abortion and in the adult during surgery. Cyclin and CDK proteins were determined by Western blot analysis. CDK activities were determined by phosphorylation amount using specific substrate.
Results:
Most cyclins and CDKs were high during the fetal period and their levels decreased at different rates during the adult period. While the protein levels of cyclin D1, cyclin D3, CDK4, CDK6 and CDK2 were still detectable in adult atria, the protein levels of cyclin E, cyclin A, cyclin B, cdc2 and PCNA were not detectable. Interestingly, p27KIP1 protein increased markedly in the adult period, while p21CIP1 protein in atria was detectable only in the fetal period. While the activities of CDK6, CDK2 and cdc2 decreased markedly, the activity of CDK4 did not change from the fetal period to the adult period.
Conclusion:
These findings indicate that marked reduction of protein levels and activities of cyclins and CDKs, and marked induction of p27KIP1 in atria, are associated with the withdrawal of cardiac cell cycle in adult humans.
Insights
Human atrial development involves reduced cyclin and cyclin-dependent kinase (CDK) levels and increased p27KIP1, signaling the end of cardiomyocyte proliferation. This study investigates key regulators of cardiac cell cycle withdrawal.
Area of Science:
- Cardiovascular Biology
- Molecular Cardiology
- Cell Cycle Regulation
Background:
- The mechanisms governing cardiomyocyte cell cycle exit and differentiation in humans are not fully understood.
- Identifying key regulators of cardiomyocyte proliferation is crucial for understanding cardiac development.
Purpose of the Study:
- To investigate the roles of specific cyclins, cyclin-dependent kinases (CDKs), and cyclin kinase inhibitors (CKIs) in human atrial development and cardiomyocyte proliferation.
- To examine protein expression and activity of these molecules during normal atrial development.
Main Methods:
- Western blot analysis was used to quantify cyclin and CDK protein levels in fetal and adult human atrial tissues.
- CDK activities were assessed by measuring the phosphorylation of specific substrates.
Main Results:
- Most cyclins and CDKs were abundant in fetal atria and decreased in adults. Cyclin D1, D3, CDK4, CDK6, and CDK2 remained detectable in adults, while others like cyclin E, A, B, cdc2, and PCNA were absent.
- p27KIP1 protein levels significantly increased in adult atria, whereas p21CIP1 was only detected in fetal tissues.
- CDK6, CDK2, and cdc2 activities markedly decreased, while CDK4 activity remained unchanged from fetal to adult stages.
Conclusions:
- A significant reduction in cyclin and CDK protein levels and activities, coupled with increased p27KIP1, is associated with the cessation of the cardiac cell cycle in adult human atria.
- These molecular changes are critical for terminal differentiation and cell cycle withdrawal in human cardiomyocytes.