Our observations indicate that PEDF induces HUVECs apoptosis through the sequential induction of PPARgamma and p53 overexpression. With the growing interest in anti-angiogenesis as a novel approach to cancer therapy, defining the mechanism of PEDF-mediated HUVEC apoptosis may facilitate the development of new therapeutics.
Retinal pigment epithelial (RPE) cells are constantly exposed to oxidative injury while clearing byproducts of photoreceptor turnover, a circumstance thought to be responsible for degenerative retinal diseases. The mechanisms of hydrogen peroxide (H(2)O(2))-induced apoptosis in RPE cells are not fully understood. We studied signal transduction mechanisms of H(2)O(2)-induced apoptosis in the human RPE cell line ARPE-19. Activation of two stress kinases (JNK and p38) occurs during H(2)O(2) stimulation, and H(2)O(2)-mediated cell death was significantly reduced by their specific inhibition. Exposure to a lethal dose of H(2)O(2) elicited Bax translocation to the mitochondria and release of apoptosis-inducing factor (AIF) from the mitochondria, both of which were abolished by either JNK- or p38-specific inhibitors. Both H(2)O(2)-induced cell death and JNK/p38 phosphorylation were partially inhibited by C. difficile toxin B, inhibitor of Rho, Rac, and cdc42. Use of pull-down assays revealed that the small GTPase activated by H(2)O(2) is Rac1. This study is the first to demonstrate that H(2)O(2) induces a Rac1/JNK1/p38 signaling cascade, and that JNK and p38 activation is important for H(2)O(2)-induced apoptosis as well as AIF/Bax translocation of RPE cells.
Human papillomavirus type 16 (HPV-16) E5 protein, along with the more publicized E6 and E7 proteins of this virus, has been found to be oncogenic. E5 is a highly hydrophobic membrane-bound protein of 83 amino acids associated with the Golgi apparatus, endoplasmic reticulum, and nuclear membrane in infected cells. E5 can activate epidermal growth factor receptor (EGFR) through binding to the 16 kD subunit of protein pump ATPase leading to a reduced downregulation of EGFR receptors. The activation of EGFR can initiate biochemical cascades that lead to overexpression of a variety of protooncogenes and stimulate rapid cell growth. Moreover, E5 can inhibit the expression of tumor suppressor gene p21((WafI/SdiI/CipI)) and impair the control of cell cycle checkpoint. E5 protein has been identified as a potential tumor vaccine target antigen.
To investigate the expression of human papillomavirus type 16 (HPV-16) E5 protein in squamous neoplastic changes in the uterine cervix, the specific E5 antibody was generated and used to identify the expression of E5 protein in 40 cases of HPV-16-positive tissues and 5 previously identified HPV-negative normal cervical tissues. The results revealed that E5 protein was primarily expressed in the lower third of the epithelium in low-grade squamous intraepithelial lesions (SILs) and throughout the whole epithelium in high-grade SILs. In invasive squamous carcinoma, 60% of HPV-16-infected cancers which contained the episomal viral genome had the E5 gene, and could express E5 protein which was located throughout the whole epithelium. Previously, we documented the expression of type I growth factor receptors [ERBB1/EGFR (epidermal growth factor receptor), ERBB2, ERBB3 and ERBB4] in the full range of cervical neoplasias by immunohistochemistry assay. Hence, in this study, we extensively analyzed the correlation between the expression of E5 protein and the expression of type I growth factor receptors. Among 40 HPV-16- infected cervical neoplasias, we found that the expression of E5 protein was significantly correlated with either the expression of the ERBB1 or the ERBB4 receptor.
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