title: The DRY box and C-terminal domain of the human cytomegalovirus US27 gene product play a role in promoting cell growth and survival.
abstract: Human cytomegalovirus (HCMV) is a widespread pathogen that can lay dormant in healthy individuals and establish lifelong latent infection. This successful co-existence is facilitated by a number of viral gene products that manipulate host cellular functions and immune responses. Among these immunomodulatory genes are four G-protein coupled receptors (GPCRs) encoded by HCMV, designated US27, US28, UL33, and UL78. Studies have shown the US28 gene product to be a functional chemokine receptor that signals both constitutively and in a ligand-dependent manner, resulting in a wide range of cellular effects. In previous work, we have found that US27 expression results in at least two biological effects: enhanced CXCR4 signaling and increased in cellular proliferation in HEK293 cells. Here, we examined the involvement of two protein domains, the DRY box and the C-terminal intracellular domain (CTD) of US27, in mediating both cell proliferation and survival. While both domains were required for a proliferative effect, loss of either domain only moderately impacted cell survival, suggesting that US27 may interact with cell survival pathways through protein regions other than the DRY box and CTD. Quantitative RT-PCR arrays were used to profile changes in cellular gene expression in the HEK293-US27 cell line, and down-regulation of cell cycle regulators CDKN1A/p21/CIP1 (cyclin dependent kinase inhibitor 1A) and SESN (Sestrin2 or Hi95) was observed. These results indicate that increased cell proliferation due to US27 may be linked to suppression of negative growth regulators, and that these interactions require the DRY box and CTD.
authors.affiliation: Department of Biology, University of San Francisco, San Francisco, California, United States of America.
authors.forename: Carolyn C
authors.initials: CC
authors.lastname: Tu
authors.affiliation: Department of Biology, University of San Francisco, San Francisco, California, United States of America.
authors.forename: Juliet V
authors.initials: JV
authors.lastname: Spencer
mesh_terms: D049109:Cell Proliferation; D002470:Cell Survival; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D003587:Cytomegalovirus / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D008856:Microscopy, Fluorescence; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary; D019707:Receptors, Chemokine / Q000737:chemistry / Q000378:metabolism*; D014162:Transfection; D014764:Viral Proteins / Q000737:chemistry / Q000378:metabolism*; D000084622:Sestrins
chemical_list: D050759:Cyclin-Dependent Kinase Inhibitor p21; D009687:Nuclear Proteins; D019707:Receptors, Chemokine; D014764:Viral Proteins; C465398:SESN2 protein, human; D000084622:Sestrins; C461644:US27 protein, human cytomegalovirus