title: c-CBL E3 ubiquitin ligase is overexpressed in cutaneous T-cell lymphoma: its inhibition promotes activation-induced cell death.
abstract: Mycosis fungoides and Sézary syndrome are two major forms of cutaneous T-cell lymphoma (CTCL) characterized by resistance to apoptosis. A central pathway for T-cell apoptosis is activation-induced cell death, which is triggered through the T-cell receptor (TCR). This results in upregulation of FAS ligand (FASL) and subsequent apoptosis through the FAS death receptor pathway. It has been known for more than a decade that TCR signaling is defective in CTCL; however, the underlying mechanism has not been apparent. In this report, we show that the E3 ubiquitin ligase, c-CBL, is overexpressed in CTCL and that its knockdown overcomes defective TCR signaling, resulting in phosphorylation of PLC-g1, calcium influx, ROS generation, upregulation of FASL, and extrinsic pathway apoptosis in CTCL cells expressing adequate FAS. In CTCL cells with suboptimal FAS expression, FAS can be upregulated epigenetically by derepression of the FAS promoter using methotrexate, which we showed previously has activity as a DNA methylation inhibitor. Using these combined strategies, FAS-low as well as FAS-high CTCL cells can be killed effectively.
authors.affiliation: Department of Dermatology, University of Wisconsin and the Middleton VA Medical Center, Madison, Wisconsin, USA.
authors.forename: Jianqiang
authors.initials: J
authors.lastname: Wu
authors.affiliation: Department of Dermatology, University of Wisconsin and the Middleton VA Medical Center, Madison, Wisconsin, USA.
authors.forename: Katrin A
authors.initials: KA
authors.lastname: Salva
authors.affiliation: Department of Dermatology, University of Wisconsin and the Middleton VA Medical Center, Madison, Wisconsin, USA. Electronic address: gwood@dermatology.wisc.edu.
authors.forename: Gary S
authors.initials: GS
authors.lastname: Wood
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D002118:Calcium / Q000378:metabolism; D045744:Cell Line, Tumor; D053222:Fas Ligand Protein / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D006801:Humans; D016410:Lymphoma, T-Cell, Cutaneous / Q000378:metabolism* / Q000473:pathology; D008297:Male; D050721:Proto-Oncogene Proteins c-cbl / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D012878:Skin Neoplasms / Q000378:metabolism* / Q000473:pathology; D015854:Up-Regulation / Q000502:physiology*
chemical_list: C505661:FASLG protein, human; D053222:Fas Ligand Protein; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D011948:Receptors, Antigen, T-Cell; D050721:Proto-Oncogene Proteins c-cbl; C067419:CBL protein, human; D002118:Calcium