home > faculty > garen

ALAN GAREN

The odd couple: A repressor protein and a retroelement RNA.
We described a novel mechanism for reversible regulation of gene transcription involving PSF, a conserved mammalian tumor-suppressor protein, and mVL30 RNA, a mouse noncoding retroelement RNA (1-4). PSF contains a DNA-binding domain (DBD) that binds to certain genes and represses transcription, and also contains RNA-binding domains (RBD) that bind mVL30 RNA, forming a complex that releases PSF from a gene and reverses repression. This regulatory mechanism has a role in oncogenesis and steroidogenesis, and probably in regulating cell proliferation during development. We isolated human retroelement RNAs that have a similar function as mVL30 RNA, which is not present in human cells. PSF belongs to a family of putative tumor-suppressor proteins containing RBD and DBD, and we are testing whether other members of this family have a similar function as PSF in regulating gene transcription. Other experiments include a molecular analysis of the protein-RNA regulatory mechanism and its normal and pathological roles.

Selected Publications
Song, X., Wang, B., Bromberg, M., Hu, Z., Konigsberg, W. and Garen A. Retroviral-mediated transmission of a mouse VL30 RNA to human melanoma cells promotes metastasis in an immunodeficient mouse model. PNAS 99, 6269-6273 (2002)

Song, X, Sui, A. and Garen, A. Binding of mouse VL30 retrotransposon RNA to PSF protein induces genes repressed by PSF: effects on steroidogenesis and oncogenesis. PNAS 101, 621-626 (2004)

Song, X., Sun, Y. and Garen, A. Roles of PSF protein and VL30 RNA in reversible gene regulation. PNAS 102, 12189-12193 (2005)

Commentary: Deisseroth, A. Normal and pathological functions of mammalian retroelements. PNAS 102, 12292-12293 (2005)

Targeting pathological blood vessels for immunotherapy of cancer and macular degeneration.
We constructed a molecule called an Icon that activates a cytolytic immune response against cells expressing the transmembrane receptor tissue factor (TF). TF is expressed on endothelial cells lining the luminal surface of pathological blood vessels in tumors. The model for the Icon molecule is a Camelid IgG1 antibody composed of two heavy chains without associated light chains, each chain containing a VH targeting domain conjugated to the Fc effector domain. The Icon is similarly composed of two chains, each chain containing fVII, the natural ligand for TF as the targeting domain conjugated to an Fc domain. The Icon binds to TF with stronger affinity and specificity than can be achieved with an anti-TF antibody. Because the Icon is synthesized by recombinant DNA technology, the fVII and Fc domains can be derived from the species of choice. Pre-clinical immunotherapy tests were done by encoding the Icon in an adenoviral vector, which was injected into a tumor in a mouse model of human metastatic cancer (1-3). The infected tumor cells synthesized and secreted the icon into the systemic circulation, and the blood-borne Icon molecules bound to TF, activating an immune response that destroyed the pathological blood vessels without harming normal vessels. A clinical trial of the protocol is being arranged for cancer patients. Similar results were obtained with a mouse model of macular degeneration (4). We are testing a nanoparticle vector as an alternative to an adenoviral vector for delivering the Icon gene

Selected Publications
Hu, Z., Sun, Y. and Garen, A. Targeting tumor vasculature endothelial cells and tumor cells for immunotherapy of human melanoma in a mouse xenograft model. PNAS 96, 8161-8166 (1999)

Hu, Z.and Garen A. Intratumoral injection of adenoviral vectors encoding tumor-targeted immunoconjugates for cancer immunotherapy. PNAS 97, 9221-9225 (2000)

Hu, Z. and Garen, A. Targeting tissue factor on tumor vascular endothelial cells and tumor cells for immunotherapy in mouse models of prostatic cancer. PNAS 98, 12180-12185 (2001)

Bora, P. S., Hu, Z., Tezel, T.H., Sohn, J.H., Kang, S.G., Cruz, J.M., Bora, N.S., Garen, A. and Kaplan, H.J. Immunotherapy for choroidal neovascularization in a laser-induced mouse model simulating exudative (wet) macular degeneration. PNAS 100, 2679-2684 (2003)

Last Updated 12-18-06