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[Cancer Research 64, 1338-1346, February 15, 2004]
© 2004 American Association for Cancer Research

Regular Articles

A Pivotal Role of Cyclic AMP-Responsive Element Binding Protein in Tumor Progression

Rinat Abramovitch1,2, Einat Tavor3, Jasmine Jacob-Hirsch5, Evelyne Zeira1, Ninette Amariglio5, Orit Pappo4, Gideon Rechavi5,6, Eithan Galun1 and Alik Honigman3

1 Goldyne Savad Institute of Gene Therapy,2 MRI/MRS Lab, HBRC,3 Department of Virology, and4 Department of Pathology, The Hebrew University-Hadassah Medical School, Jerusalem, Israel, and5 Department of Pediatric Hemato-Oncology, Safra Children’s Hospital, Sheba Medical Center and6 Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel

Tumor microenvironment controls the selection of malignant cells capable of surviving in stressful and hypoxic conditions. The transcription factor, cyclic AMP-responsive element binding (CREB) protein, activated by multiple extracellular signals, modulates cellular response by regulating the expression of a multitude of genes. Previously, we have demonstrated that two cystein residues, at the DNA binding domain of CREB, mediate activation of CREB-dependent gene expression at normoxia and hypoxia. The construction of a dominant-positive CREB mutant, insensitive to hypoxia cue (substitution of two cystein residues at position 300 and 310 with serine in the DNA binding domain) and of a dominant negative CREB mutant (addition of a mutation in serine133), enabled a direct assessment, in vitro and in vivo, of the role of CREB in tumor progression. In this work, we demonstrate both in vitro and in vivo that CREB controls hepatocellular carcinoma growth, supports angiogenesis, and renders resistance to apoptosis. Along with the identification, by DNA microarray, of the CREB-regulated genes in normoxia and hypoxia, this work demonstrates for the first time that in parallel to other hypoxia responsive mechanisms, CREB plays an important role in hepatocellular carcinoma tumor progression.




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