The tumor suppressor p53 represses the proto-oncogene c-Myc through the induction of the tumor suppressor miR-145. This study shows that miR-145 is expressed via the PI-3K/Akt and p53 pathways. p53 transcriptionally induces miR-145 by interacting with a potential p53 response element in the miR-145 promoter. miR-145 directly targets c-Myc, leading to its suppression. This silencing of c-Myc by miR-145 contributes to the inhibition of tumor cell growth both in vitro and in vivo. Furthermore, blocking miR-145 with anti-miR-145 reverses the p53-mediated repression of c-Myc. These findings define miR-145 as a key component of the p53 regulatory network, providing a direct link between p53 and c-Myc in gene regulation. miR-145 is a new member of the p53 regulatory network and plays a critical role in the posttranscriptional regulation of c-Myc by p53. The study highlights the importance of miR-145 in tumor suppression and provides new insights into the p53-mediated regulation of c-Myc. The results suggest that miR-145 is essential for maintaining the balance between p53 and c-Myc, which is crucial for normal cell growth and proliferation. Disruption of this balance, such as down-regulation of miR-145, can lead to cell malignancy. The study also demonstrates that miR-145 can suppress c-Myc in p53-deficient cells, indicating that miR-145-mediated c-Myc repression can be independent of p53 when sufficient miR-145 is present. These findings contribute to the understanding of the complex regulatory network involving p53 and c-Myc, and highlight the role of miR-145 in tumor suppression.The tumor suppressor p53 represses the proto-oncogene c-Myc through the induction of the tumor suppressor miR-145. This study shows that miR-145 is expressed via the PI-3K/Akt and p53 pathways. p53 transcriptionally induces miR-145 by interacting with a potential p53 response element in the miR-145 promoter. miR-145 directly targets c-Myc, leading to its suppression. This silencing of c-Myc by miR-145 contributes to the inhibition of tumor cell growth both in vitro and in vivo. Furthermore, blocking miR-145 with anti-miR-145 reverses the p53-mediated repression of c-Myc. These findings define miR-145 as a key component of the p53 regulatory network, providing a direct link between p53 and c-Myc in gene regulation. miR-145 is a new member of the p53 regulatory network and plays a critical role in the posttranscriptional regulation of c-Myc by p53. The study highlights the importance of miR-145 in tumor suppression and provides new insights into the p53-mediated regulation of c-Myc. The results suggest that miR-145 is essential for maintaining the balance between p53 and c-Myc, which is crucial for normal cell growth and proliferation. Disruption of this balance, such as down-regulation of miR-145, can lead to cell malignancy. The study also demonstrates that miR-145 can suppress c-Myc in p53-deficient cells, indicating that miR-145-mediated c-Myc repression can be independent of p53 when sufficient miR-145 is present. These findings contribute to the understanding of the complex regulatory network involving p53 and c-Myc, and highlight the role of miR-145 in tumor suppression.