mda- 7 (IL-24) mediates selective apoptosis in human melanoma cells by inducing the coordinated overexpression of the GADD family of genes by means of p38 MAPK

• DOI: 10.1073/pnas.152327199
• Publication Date: 2002-07-28T22:26:28Z
• Authors: Devanand Sarkar; Zao-Zhong Su; Irina V. Lebedeva; Moira Sauane; Rahul V. Gopalkri...; Kristoffer Valerie; Paul Dent; Paul B. Fisher
• Keywords: Gadd45

Subtraction hybridization identified melanoma differentiation-associated gene-7 (mda-7) as a gene induced during terminal differentiation in human cells. On the basis of structure, chromosomal localization and cytokine-like properties, mda-7 is classified IL-24. Administration mda-7/IL-24 by means replication-incompetent adenovirus (Ad.mda-7) induces apoptosis selectively diverse cancer cells without inducing harmful effects normal fibroblast or epithelial The present studies investigated mechanism underlying this differential apoptotic effect. Infection cells, but not immortal melanocytes, with Ad.mda-7 time- dose-dependent increase expression, mRNA protein, family growth arrest DNA damage (GADD)-inducible genes, which correlated induction apoptosis. Among members GADD GADD153, GADD45 alpha, GADD34 displayed marked, gamma showed minimal induction. Treatment SB203580, selective inhibitor p38 mitogen-activated protein kinase (MAPK) pathway, effectively inhibited Ad.mda-7-induced Additional support for an involvement MAPK pathway Ad.mda-7-mediated was documented using expressing dominant negative mutant MAPK. increased phosphorylation heat shock 27 melanocytes. In addition, SB203580 genes manner, it blocked down-regulation antiapoptotic BCL-2. Inhibition antisense approach either alone combination also These results hypothesis that mediates thereby resulting