The article investigates the expression of p21, a cyclin-dependent kinase inhibitor, in various contexts, including cell growth, differentiation, and DNA damage. Key findings include: 1. **p21 Expression Independent of p53**: p21 expression can occur in the absence of functional p53 in various tissues during development and in adult mice. However, p53 is essential for p21 induction following exposure to γ irradiation. 2. **p21 Expression During Differentiation**: p21 is up-regulated in murine erythroleukemia (MEL) cells during differentiation, suggesting a role in growth arrest before terminal differentiation. The kinetics of p21 induction in MEL cells indicate that it may be involved in the G1 phase arrest. 3. **p21 Serum Induction**: p21 is serum inducible in both wild-type and p53-deficient fibroblasts, but with different kinetics and levels. Cycloheximide superinduces p21 expression in wild-type cells, suggesting post-transcriptional regulation. 4. **p21 Promoter Analysis**: The p21 promoter region contains critical p53-binding sites, and the serum responsiveness of the promoter maps to a region overlapping with a p53-binding site. This region also contains a putative Ets-binding site, which may be involved in serum induction. 5. **p21 and Cyclin/Cdk Activity**: p21-associated H1 kinase activity increases as cells are serum-stimulated, supporting its role in promoting cyclin/cdk complex assembly. 6. **Discussion**: p21 is regulated by factors independent of p53 in multiple contexts, including serum release, differentiation, and adult and embryonic tissues. These regulations are both transcriptional and post-transcriptional and are subject to homeostatic control. The study highlights the complex regulation of p21 and its potential roles in various cellular processes, emphasizing the importance of understanding the mechanisms underlying p21 induction in different scenarios.The article investigates the expression of p21, a cyclin-dependent kinase inhibitor, in various contexts, including cell growth, differentiation, and DNA damage. Key findings include: 1. **p21 Expression Independent of p53**: p21 expression can occur in the absence of functional p53 in various tissues during development and in adult mice. However, p53 is essential for p21 induction following exposure to γ irradiation. 2. **p21 Expression During Differentiation**: p21 is up-regulated in murine erythroleukemia (MEL) cells during differentiation, suggesting a role in growth arrest before terminal differentiation. The kinetics of p21 induction in MEL cells indicate that it may be involved in the G1 phase arrest. 3. **p21 Serum Induction**: p21 is serum inducible in both wild-type and p53-deficient fibroblasts, but with different kinetics and levels. Cycloheximide superinduces p21 expression in wild-type cells, suggesting post-transcriptional regulation. 4. **p21 Promoter Analysis**: The p21 promoter region contains critical p53-binding sites, and the serum responsiveness of the promoter maps to a region overlapping with a p53-binding site. This region also contains a putative Ets-binding site, which may be involved in serum induction. 5. **p21 and Cyclin/Cdk Activity**: p21-associated H1 kinase activity increases as cells are serum-stimulated, supporting its role in promoting cyclin/cdk complex assembly. 6. **Discussion**: p21 is regulated by factors independent of p53 in multiple contexts, including serum release, differentiation, and adult and embryonic tissues. These regulations are both transcriptional and post-transcriptional and are subject to homeostatic control. The study highlights the complex regulation of p21 and its potential roles in various cellular processes, emphasizing the importance of understanding the mechanisms underlying p21 induction in different scenarios.