Functional Identification of Distinct Sets of Antitumor Activities Mediated by the FKBP Gene Family

• Published in: Proceedings of the National Academy of Sciences - PNAS 2003-11, Vol.100 (24), p.14253-14258
• Main Authors: Fong, Sylvia, Mounkes, Leslie, Liu, Yong, Maibaum, Michael, Alonzo, Eric, Desprez, Pierre-Yves, Thor, Ann D., Kashani-Sabet, Mohammed, Debs, Robert J.
• Format: Article
• Language: English
• Subjects: Animals; Base Sequence; Biological Sciences; Cell Adhesion - genetics; Cell lines; DNA, Complementary - genetics; FK-506-binding protein; Fkbp1a protein; Fkbp8 protein; Gene Expression; Gene expression regulation; Genes; Genes, Tumor Suppressor; Genetics; Lungs; Medical research; Melanoma, Experimental - genetics; Melanoma, Experimental - pathology; Melanoma, Experimental - secondary; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Multigene Family; Neoplasm Invasiveness - genetics; Plasmids; RNA Interference; Sirolimus - pharmacology; syndecan 1; T lymphocytes; Tacrolimus Binding Protein 1A - genetics; Tacrolimus Binding Proteins - genetics; Tumor cell line; Tumors
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2332307100

Assigning biologic function to the many sequenced but still uncharacterized genes remains the greatest obstacle confronting the human genome project. Differential gene expression profiling routinely detects uncharacterized genes aberrantly expressed in conditions such as cancer but cannot determine which genes are functionally involved in such complex phenotypes. Integrating gene expression profiling with specific modulation of gene expression in relevant disease models can identify complex biologic functions controlled by currently uncharacterized genes. Here, we used systemic gene transfer in tumor-bearing mice to identify novel antiinvasive and antimetastatic functions for Fkbp8, and subsequently for Fkbp1a. Fkbp8 is a previously uncharacterized member of the FK-506-binding protein (FKBP) gene family down-regulated in aggressive tumors. Antitumor effects produced by Fkbp1a gene expression are mediated by cellular pathways entirely distinct from those responsible for antitumor effects produced by Fkbp1a binding to its bacterially derived ligand, rapamycin. We then used gene expression profiling to identify syndecan 1 (Sdc1) and matrix metalloproteinase 9 (MMP9) as genes directly regulated by Fkbp1a and Fkbp8. FKBP gene expression coordinately induces the expression of the antiinvasive Sdc1 gene and suppresses the proinvasive MMP9 gene. Conversely, short interfering RNA-mediated suppression of Fkbp1a increases tumor cell invasion and MMP9 levels, while down-regulating Sdc1. Thus, syndecan 1 and MMP9 appear to mediate the antiinvasive and antimetastatic effects produced by FKBP gene expression. These studies show that uncharacterized genes differentially expressed in metastatic cancers can play important functional roles in the metastatic phenotype. Furthermore, identifying gene regulatory networks that function to control tumor progression may permit more accurate modeling of the complex molecular mechanisms of this disease.