Showing papers by "Sam W. Lee published in 2001"

Pin1 is overexpressed in breast cancer and cooperates with Ras signaling in increasing the transcriptional activity of c-Jun towards cyclin D1

Abstract: Phosphorylation on serines or threonines preceding proline (Ser/Thr-Pro) is a major signaling mechanism. The conformation of a subset of phosphorylated Ser/Thr-Pro motifs is regulated by the prolyl isomerase Pin1. Inhibition of Pin1 induces apoptosis and may also contribute to neuronal death in Alzheimer's disease. However, little is known about the role of Pin1 in cancer or in modulating transcription factor activity. Here we report that Pin1 is strikingly overexpressed in human breast cancers, and that its levels correlate with cyclin D1 levels in tumors. Overexpression of Pin1 increases cellular cyclin D1 protein and activates its promoter. Furthermore, Pin1 binds c-Jun that is phosphorylated on Ser63/73-Pro motifs by activated JNK or oncogenic Ras. Moreover, Pin1 cooperates with either activated Ras or JNK to increase transcriptional activity of c-Jun towards the cyclin D1 promoter. Thus, Pin1 is up-regulated in human tumors and cooperates with Ras signaling in increasing c-Jun transcriptional activity towards cyclin D1. Given the crucial roles of Ras signaling and cyclin D1 overexpression in oncogenesis, our results suggest that overexpression of Pin1 may promote tumor growth.

p53 induction of heparin-binding EGF-like growth factor counteracts p53 growth suppression through activation of MAPK and PI3K/Akt signaling cascades

Abstract: Tumor suppressor p53 induction in response to cellular stresses activates the mitogen-activated protein kinase (MAPK) cascade through pathways involving Ras and RAF: p53's ability to activate this pathway is dependent on p53-mediated transcription. In order to investigate potential p53 target gene(s) involved, we utilized expression array analysis and identified heparin-binding epidermal growth factor-like growth factor (HB-EGF) as being markedly up-regulated by p53. In response to DNA damage, HB-EGF was induced in wild-type, but not in mutant p53-containing cells, implying its p53 dependence. HB-EGF neutralizing antibody and inhibitors of EGF receptor signaling abrogated p53-induced MAPK activation. Expression of HB-EGF was shown to protect cells from H(2)O(2)-induced apoptosis through MAPK activation. Additionally, the PI3K/Akt pathway was activated in response to p53 signaling through HB-EGF induction, and inhibition of MAPK and Akt activation after DNA damage decreased cell survival in wild-type p53-containing cells. All these findings point to a novel aspect of p53 function. Namely, p53-induced growth factors such as HB-EGF, which activate MAPK and Akt signaling, may be involved in a compensatory mechanism to alleviate adverse effects of cellular stresses.

Loss of H-cadherin protein expression in human non-small cell lung cancer is associated with tumorigenicity

Abstract: Abnormalities in the H-cadherin gene have been described in several human cancers. However, their biological significance remains undetermined. To investigate the role of H-cadherin in non-small cell lung cancer (NSCLC), a chimera H-cadherin-green fluorescent protein (GFP) expressed in Cos-7 cells was used to identify an anti-H- cadherin antibody, HCD-1. Western blot analysis was performed in six NSCLC cell lines and 35 pairs of primary NSCLC tumors and nonmalignant lung tissue obtained from surgical resections using HCD-1. Loss of H-cadherin expression was seen in five (83%) of the six NSCLC cell lines, whereas loss of E-cadherin was seen in three (50%) of the six. H-cadherin expression was lost in 15 (43%) of 35 NSCLC surgical tumor specimens, whereas E-cadherin expression was lost in 6 (17%) of 35. H-cadherin was expressed in all of the nonmalignant lung tissue from all of the surgical specimens. Fourteen of 35 tumors were heterotransplanted s.c. in nude mice. Tumorigenicity in nude mice was associated with both loss of H-cadherin expression (P = 0.03) and loss of E-cadherin expression (P = 0.05). Loss of H-cadherin was also associated with a more advanced local tumor growth, although the difference was not significant. The results indicate that loss of H-cadherin is frequent in human NSCLC and suggest that it facilitates the implantation and local growth of human NSCLC tumors.