Showing papers by "Sam W. Lee published in 2002"
TL;DR: The cyclin-dependent kinase (CDK) inhibitor p21 (Waf1/Cip1/Sdi1) was identified initially as a gene induced in senescent cells and itself has been shown to cause permanent growth arrest/senescence as discussed by the authors.
Abstract: The cyclin-dependent kinase (CDK) inhibitor p21(Waf1/Cip1/Sdi1) was identified initially as a gene induced in senescent cells and itself has been shown to cause permanent growth arrest/senescence. Reactive oxygen species (ROS), a byproduct of oxidative processes, can also induce an irreversible growth arrest similar to senescence. Here we show that p21 increased intracellular levels of ROS both in normal fibroblasts and in p53-negative cancer cells. N-acetyl-L-cysteine, an ROS inhibitor, rescued p21-induced senescence, showing that ROS elevation is necessary for induction of the permanent growth arrest phenotype. p16(Ink4a), a CDK4- and CDK6-specific inhibitor, failed to increase ROS levels, and cell cycle arrest induced by p16 was reversible following its down-regulation, demonstrating the specificity of this p21 effect. A p21 mutant that lacked the ability to bind proliferating cell nuclear antigen (PCNA) retained the ability to induce both ROS and permanent growth arrest. All of these findings establish that p21 mediates senescence by a mechanism involving ROS accumulation which does not require either its PCNA binding or the CDK inhibitory functions shared with p16.
329 citations
TL;DR: It is demonstrated that Pin1 expression is mediated by the transcription factor E2F and enhanced by c-Neu and Ha-Ras via E2f and not only confers transforming properties on mammary epithelial cells but also enhances the transformed phenotypes of Neu/Ras-transformed mammary intestinal cells.
Abstract: Oncogenes Neu/HER2/ErbB2 and Ras can induce mammary tumorigenesis via upregulation of cyclin D1. One major regulatory mechanism in these oncogenic signaling pathways is phosphorylation of serines or threonines preceding proline (pSer/Thr-Pro). Interestingly, the pSer/Thr-Pro motifs in proteins exist in two completely distinct cis and trans conformations, whose conversion is catalyzed specifically by the essential prolyl isomerase Pin1. By isomerizing pSer/Thr-Pro bonds, Pin1 can regulate the conformation and function of certain phosphorylated proteins. We have previously shown that Pin1 is overexpressed in breast tumors and positively regulates cyclin D1 by transcriptional activation and posttranslational stabilization. Moreover, in Pin1 knockout mice, mammary epithelial cells fail to undergo massive proliferation during pregnancy, as is the case in cyclin D1 null mice. These results indicate that Pin1 is upregulated in breast cancer and may be involved in mammary tumors. However, the mechanism of Pin1 overexpression in cancer and its significance in cell transformation remain largely unknown. Here we demonstrate that PIN1 expression is mediated by the transcription factor E2F and enhanced by c-Neu and Ha-Ras via E2F. Furthermore, overexpression of Pin1 not only confers transforming properties on mammary epithelial cells but also enhances the transformed phenotypes of Neu/Ras-transformed mammary epithelial cells. In contrast, inhibition of Pin1 suppresses Neu- and Ras-induced transformed phenotypes, which can be fully rescued by overexpression of a constitutively active cyclin D1 mutant that is refractory to the Pin1 inhibition. Thus, Pin1 is an E2F target gene that is essential for the Neu/Ras-induced transformation of mammary epithelial cells through activation of cyclin D1.
252 citations
TL;DR: A new role is demonstrated in regulating p53 function during DNA damage that depended on the WW domain in Pin1 and Ser33/46-Pro motifs in p53, and Pin1 regulates the stability of p53 and its transcriptional activity toward the p21 promoter.
229 citations
TL;DR: Results demonstrate that Cox‐2 is induced by p53‐mediated activation of the Ras/Raf/ERK cascade, counteracting p 53‐mediated apoptosis, and this anti‐apoptosis effect may be a mechanism to abate cellular stresses associated with p53 induction.
Abstract: The identification of transcriptional targets of the tumor suppressor p53 is crucial in understanding mechanisms by which it affects cellular outcomes. Through expression array analysis, we identified cyclooxygenase 2 (Cox‐2), whose expression was inducible by wild‐type p53 and DNA damage. We also found that p53‐induced Cox‐2 expression results from p53‐mediated activation of the Ras/Raf/MAPK cascade, as demonstrated by suppression of Cox‐2 induction in response to p53 by dominant‐negative Ras or Raf1 mutants. Furthermore, heparin‐binding epidermal growth factor‐like growth factor (HB‐ EGF), a p53 downstream target gene, induced Cox‐2 expression, implying that Cox‐2 is an ultimate effector in the p53→HB‐EGF→Ras/Raf/MAPK→Cox‐2 pathway. p53‐induced apoptosis was enhanced greatly in Cox‐2 knock‐out cells as compared with wild‐type cells, suggesting that Cox‐2 has an abrogating effect on p53‐induced apoptosis. Also, a selective Cox‐2 inhibitor, NS‐398, significantly enhanced genotoxic stress‐induced apoptosis in several types of p53+/+ normal human cells, through a caspase‐dependent pathway. Together, these results demonstrate that Cox‐2 is induced by p53‐mediated activation of the Ras/Raf/ERK cascade, counteracting p53‐mediated apoptosis. This anti‐apoptosis effect may be a mechanism to abate cellular stresses associated with p53 induction.
207 citations