title: The protective role of a small GTPase RhoE against UVB-induced DNA damage in keratinocytes.
abstract: RhoE, a p53 target gene, was identified as a critical factor for the survival of human keratinocytes in response to UVB. The Rho family of GTPases regulates many aspects of cellular behavior through alterations to the actin cytoskeleton, acting as molecular switches cycling between the active, GTP-bound and the inactive, GDP-bound conformations. Unlike typical Rho family proteins, RhoE (also known as Rnd3) is GTPase-deficient and thus expected to be constitutively active. In this study, we investigated the response of cultured human keratinocyte cells to UVB irradiation. RhoE protein levels increase upon exposure to UVB, and ablation of RhoE induction through small interfering RNA resulted in a significant increase in apoptosis and a reduction in the levels of the pro-survival targets p21, Cox-2, and cyclin D1, as well as an increase of reactive oxygen species levels when compared with control cells. These data indicate that RhoE is a pro-survival factor acting upstream of p38, JNK, p21, and cyclin D1. HaCat cells expressing small interfering RNA to p53 indicate that RhoE functions independently of its known associates, p53 and Rho-associated kinase I (ROCK I). Targeted expression of RhoE in epidermis using skin-specific transgenic mouse model resulted in a significant reduction in the number of apoptotic cells following UVB irradiation. Thus, RhoE induction counteracts UVB-induced apoptosis and may serve as a novel target for the prevention of UVB-induced photodamage regardless of p53 status.
authors.affiliation: Dermatology Division, University of Washington, Seattle, Washington 98109.
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Boswell
authors.affiliation: Cutaneous Biology Research Center (CBRC), Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129 and the.
authors.forename: Pat P
authors.initials: PP
authors.lastname: Ongusaha
authors.affiliation: Dermatology Division, University of Washington, Seattle, Washington 98109.
authors.forename: Paul
authors.initials: P
authors.lastname: Nghiem
authors.affiliation: Cutaneous Biology Research Center (CBRC), Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129 and the. Electronic address: sam.lee@cbrc2.mgh.harvard.edu.
authors.forename: Sam W
authors.initials: SW
authors.lastname: Lee
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects*; D002470:Cell Survival; D019938:Cyclin D1 / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D004249:DNA Damage / Q000187:drug effects / Q000528:radiation effects*; D006153:Guanosine Diphosphate / Q000378:metabolism; D006160:Guanosine Triphosphate / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D015603:Keratinocytes / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000378:metabolism; D014466:Ultraviolet Rays / Q000009:adverse effects; D054462:p21-Activated Kinases; D020741:rho GTP-Binding Proteins / Q000378:metabolism*; D054460:rho-Associated Kinases
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53; D019938:Cyclin D1; D006153:Guanosine Diphosphate; D006160:Guanosine Triphosphate; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D017346:Protein Serine-Threonine Kinases; D054462:p21-Activated Kinases; D054460:rho-Associated Kinases; C508705:RND3 protein, human; D020741:rho GTP-Binding Proteins