The tumor suppressor protein p53 is a key regulator of cell survival and death in response to various stresses, including DNA damage and oncogene activation. While p53 is primarily known for its nuclear functions as a transcription factor that regulates genes involved in apoptosis, cell cycle arrest, and DNA repair, it also has cytoplasmic functions that are increasingly recognized. In the cytoplasm, p53 can trigger apoptosis and inhibit autophagy, contributing to its role as a tumor suppressor. p53 exerts its effects through both transcriptional and non-transcriptional mechanisms. In the nucleus, p53 binds to DNA and activates the transcription of genes involved in apoptosis and cell cycle regulation. In the cytoplasm, p53 can induce apoptosis independently of transcription, as demonstrated by studies showing that transactivation-deficient p53 mutants can still trigger apoptosis. This cytoplasmic activity is further supported by the ability of p53 to interact with Bcl-2 family proteins, which are involved in mitochondrial membrane permeabilization and apoptosis. Cytoplasmic p53 can also influence mitochondrial function by inducing mitochondrial outer membrane permeabilization (MOMP), leading to the release of pro-apoptotic factors. This process is regulated by interactions between p53 and Bcl-2 family proteins, such as Bcl-XL and Bak. p53 can act as a direct activator of Bax and Bak or as a sensitizer that enhances their activity. Additionally, p53 can inhibit autophagy by suppressing the AMP-activated protein kinase (AMPK) and activating the mammalian target of rapamycin (mTOR), which are key regulators of autophagy. The regulation of p53's cytoplasmic functions is influenced by post-translational modifications, including ubiquitination and acetylation, which affect its subcellular localization and activity. The balance between nuclear and cytoplasmic p53 is crucial for maintaining cellular homeostasis and preventing oncogenesis. Mutations in p53, particularly in the DNA binding domain, can disrupt its ability to induce apoptosis and MOMP while preserving its inhibitory effect on autophagy, contributing to tumorigenesis. The interplay between nuclear and cytoplasmic p53 functions is essential for the coordinated regulation of apoptosis and autophagy. The cytoplasmic p53 pathway can be selectively inhibited to protect against radiation-induced cell death, highlighting its importance in cancer therapy. Understanding the complex roles of p53 in both nuclear and cytoplasmic contexts is crucial for developing targeted therapies for cancer and related diseases.The tumor suppressor protein p53 is a key regulator of cell survival and death in response to various stresses, including DNA damage and oncogene activation. While p53 is primarily known for its nuclear functions as a transcription factor that regulates genes involved in apoptosis, cell cycle arrest, and DNA repair, it also has cytoplasmic functions that are increasingly recognized. In the cytoplasm, p53 can trigger apoptosis and inhibit autophagy, contributing to its role as a tumor suppressor. p53 exerts its effects through both transcriptional and non-transcriptional mechanisms. In the nucleus, p53 binds to DNA and activates the transcription of genes involved in apoptosis and cell cycle regulation. In the cytoplasm, p53 can induce apoptosis independently of transcription, as demonstrated by studies showing that transactivation-deficient p53 mutants can still trigger apoptosis. This cytoplasmic activity is further supported by the ability of p53 to interact with Bcl-2 family proteins, which are involved in mitochondrial membrane permeabilization and apoptosis. Cytoplasmic p53 can also influence mitochondrial function by inducing mitochondrial outer membrane permeabilization (MOMP), leading to the release of pro-apoptotic factors. This process is regulated by interactions between p53 and Bcl-2 family proteins, such as Bcl-XL and Bak. p53 can act as a direct activator of Bax and Bak or as a sensitizer that enhances their activity. Additionally, p53 can inhibit autophagy by suppressing the AMP-activated protein kinase (AMPK) and activating the mammalian target of rapamycin (mTOR), which are key regulators of autophagy. The regulation of p53's cytoplasmic functions is influenced by post-translational modifications, including ubiquitination and acetylation, which affect its subcellular localization and activity. The balance between nuclear and cytoplasmic p53 is crucial for maintaining cellular homeostasis and preventing oncogenesis. Mutations in p53, particularly in the DNA binding domain, can disrupt its ability to induce apoptosis and MOMP while preserving its inhibitory effect on autophagy, contributing to tumorigenesis. The interplay between nuclear and cytoplasmic p53 functions is essential for the coordinated regulation of apoptosis and autophagy. The cytoplasmic p53 pathway can be selectively inhibited to protect against radiation-induced cell death, highlighting its importance in cancer therapy. Understanding the complex roles of p53 in both nuclear and cytoplasmic contexts is crucial for developing targeted therapies for cancer and related diseases.