title: Caspase-3-resistant uncleavable form of acidic leucine-rich nuclear phosphoprotein 32B potentiates leukemic cell apoptosis.
abstract: One member of the highly conserved acidic leucine‑rich nuclear phosphoprotein 32 kDa (ANP32) family of proteins, ANP32B, is critical for normal development, as demonstrated by a study in ANP32B‑deficient mice. Another study indicated that ANP32B was a direct substrate of caspase‑3, and was primarily cleaved at the sequence Ala‑Glu‑Val‑Asp, following Asp‑163. To investigate the significance of ANP32B cleavage in apoptosis, leukemic U937T cell lines were generated with inducible expression of ANP32B(wild type; WT), the uncleavable mutant ANP32B(D163A) and the N‑terminal fragment ANP32B(1‑163). Notably, overexpression of ANP32B(WT) and ANP32B(D163A) moderately increased and significantly enhanced etoposide‑induced apoptosis and caspase‑3 activation, whereas expression of ANP32B(1‑163) produced no effect. Two hypotheses have been generated, which may explain the distinct roles of the various ANP32B forms: i) ANP32B(WT) and ANP32B(D163A) localize in the nucleus while ANP32B(1‑163) mainly resides in the cytosol; or ii) ANP32B(WT) and ANP32B(D163A), but not ANP32B(1‑163), inhibit the expression of the anti‑apoptotic protein Bcl‑2. Based on these observations, caspase‑3‑resistant uncleavable ANP32B(D163A) is hypothesized to be pro‑apoptotic in leukemic cells.
authors.affiliation: Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Center of Molecular Medicine, Rui‑Jin Hospital, Shanghai Jiao‑Tong University School of Medicine, Shanghai 200025, P.R. China.
authors.forename: Cai-Xia
authors.initials: CX
authors.lastname: Li
authors.affiliation: Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Center of Molecular Medicine, Rui‑Jin Hospital, Shanghai Jiao‑Tong University School of Medicine, Shanghai 200025, P.R. China.
authors.forename: Shao-Ming
authors.initials: SM
authors.lastname: Shen
authors.affiliation: Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Center of Molecular Medicine, Rui‑Jin Hospital, Shanghai Jiao‑Tong University School of Medicine, Shanghai 200025, P.R. China.
authors.forename: Li-Shun
authors.initials: LS
authors.lastname: Wang
authors.affiliation: Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Center of Molecular Medicine, Rui‑Jin Hospital, Shanghai Jiao‑Tong University School of Medicine, Shanghai 200025, P.R. China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Yu
mesh_terms: D017209:Apoptosis / Q000235:genetics; D053148:Caspase 3 / Q000378:metabolism*; D045744:Cell Line, Tumor; D015870:Gene Expression; D006801:Humans; D007930:Leucine; D007938:Leukemia / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D054730:Protein Interaction Domains and Motifs / Q000235:genetics; D051745:Protein Kinase C-delta / Q000378:metabolism; D059748:Proteolysis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism
chemical_list: C490341:ANP32B protein, human; D009687:Nuclear Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051745:Protein Kinase C-delta; D053148:Caspase 3; D007930:Leucine