title: The inhibitor of growth protein 5 (ING5) depends on INCA1 as a co-factor for its antiproliferative effects.
abstract: The proteins of the Inhibitor of Growth (ING) family are involved in multiple cellular functions such as cell cycle regulation, apoptosis, and chromatin remodeling. For ING5, its actual role in growth suppression and the necessary partners are not known. In a yeast-two-hybrid approach with human bone marrow derived cDNA, we identified ING5 as well as several other proteins as interaction partners of Inhibitor of cyclin A1 (INCA1) that we previously characterized as a novel interaction partner of cyclin A1/CDK2. ING5 expression in leukemic AML blasts was severely reduced compared to normal bone marrow. In line, ING5 inhibited bone marrow colony formation upon retroviral transduction. However, Inca1(-/-) bone marrow colony formation was not suppressed by ING5. In murine embryonic fibroblast (MEF) cells from Inca1(+/+) and Inca1(-/-) mice, overexpression of ING5 suppressed cell proliferation only in the presence of INCA1, while ING5 had no effect in Inca1(-/-) MEFs. ING5 overexpression induced a delay in S-phase progression, which required INCA1. Finally, ING5 overexpression enhanced Fas-induced apoptosis in Inca1(+/+) MEFs, while Inca1(-/-) MEFs were protected from Fas antibody-induced apoptosis. Taken together, these results indicate that ING5 is a growth suppressor with suppressed expression in AML whose functions depend on its interaction with INCA1.
authors.affiliation: Department of Medicine, Hematology/Oncology, University of Münster, Münster, Germany.
authors.forename: Feng
authors.initials: F
authors.lastname: Zhang
authors.forename: Nicole
authors.initials: N
authors.lastname: Bäumer
authors.forename: Miriam
authors.initials: M
authors.lastname: Rode
authors.forename: Ping
authors.initials: P
authors.lastname: Ji
authors.forename: Tao
authors.initials: T
authors.lastname: Zhang
authors.forename: Wolfgang E
authors.initials: WE
authors.lastname: Berdel
authors.forename: Carsten
authors.initials: C
authors.lastname: Müller-Tidow
mesh_terms: D000208:Acute Disease; D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D019556:COS Cells; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002453:Cell Cycle; D049109:Cell Proliferation; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism; D004622:Embryo, Mammalian / Q000166:cytology; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D005434:Flow Cytometry; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D007951:Leukemia, Myeloid / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D020798:Two-Hybrid System Techniques
chemical_list: D002352:Carrier Proteins; C492512:INCA1 protein, human; C508131:ING5 protein, human; D010750:Phosphoproteins; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D051357:Cyclin-Dependent Kinase 2