title: Heat shock protein 70 regulates Tcl1 expression in leukemia and lymphomas.
abstract: T-cell leukemia/lymphoma 1 (TCL1) is an oncogene overexpressed in T-cell prolymphocytic leukemia and in B-cell malignancies including B-cell chronic lymphocytic leukemia and lymphomas. To date, only a limited number of Tcl1-interacting proteins that regulate its oncogenic function have been identified. Prior studies used a proteomic approach to identify a novel interaction between Tcl1 with Ataxia Telangiectasia Mutated. The association of Tcl1 and Ataxia Telangiectasia Mutated leads to activation of the NF-κB pathway. Here, we demonstrate that Tcl1 also interacts with heat shock protein (Hsp) 70. The Tcl1-Hsp70 complex was validated by coimmunoprecipitation experiments. In addition, we report that Hsp70, a protein that plays a critical role in the folding and maturation of several oncogenic proteins, associates with Tcl1 protein and stabilizes its expression. The inhibition of the ATPase activity of Hsp70 results in ubiquitination and proteasome-dependent degradation of Tcl1. The inhibition of Hsp70 significantly reduced the growth of lymphoma xenografts in vivo and down-regulated the expression of Tcl1 protein. Our findings reveal a functional interaction between Tcl1 and Hsp70 and identify Tcl1 as a novel Hsp70 client protein. These findings suggest that inhibition of Hsp70 may represent an alternative effective therapy for chronic lymphocytic leukemia and lymphomas via its ability to inhibit the oncogenic functions of Tcl1.
authors.affiliation: Department of Molecular Immunology, Virology, and Medical Genetics, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Eugenio
authors.initials: E
authors.lastname: Gaudio
authors.forename: Francesco
authors.initials: F
authors.lastname: Paduano
authors.forename: Apollinaire
authors.initials: A
authors.lastname: Ngankeu
authors.forename: Francesca
authors.initials: F
authors.lastname: Lovat
authors.forename: Muller
authors.initials: M
authors.lastname: Fabbri
authors.forename: Hui-Lung
authors.initials: HL
authors.lastname: Sun
authors.forename: Pierluigi
authors.initials: P
authors.lastname: Gasparini
authors.forename: Alexey
authors.initials: A
authors.lastname: Efanov
authors.forename: Yong
authors.initials: Y
authors.lastname: Peng
authors.forename: Nicola
authors.initials: N
authors.lastname: Zanesi
authors.forename: Mohammed A
authors.initials: MA
authors.lastname: Shuaib
authors.forename: Laura Z
authors.initials: LZ
authors.lastname: Rassenti
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Kipps
authors.forename: Chenglong
authors.initials: C
authors.lastname: Li
authors.forename: Rami I
authors.initials: RI
authors.lastname: Aqeilan
authors.forename: Gregory B
authors.initials: GB
authors.lastname: Lesinski
authors.forename: Francesco
authors.initials: F
authors.lastname: Trapasso
authors.forename: Carlo M
authors.initials: CM
authors.lastname: Croce
mesh_terms: D000818:Animals; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D020287:In Situ Nick-End Labeling; D007938:Leukemia / Q000235:genetics / Q000378:metabolism*; D008223:Lymphoma / Q000235:genetics / Q000378:metabolism*; D013058:Mass Spectrometry; D051379:Mice; D008807:Mice, Inbred BALB C; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D014183:Transplantation, Heterologous
chemical_list: D018840:HSP70 Heat-Shock Proteins; D011518:Proto-Oncogene Proteins; C090851:TCL1A protein, human