Journal Article

Downregulation of ANP32B, a novel substrate of caspase-3, enhances caspase-3 activation and apoptosis induction in myeloid leukemic cells

Shao-Ming Shen, Yun Yu, Ying-Li Wu, Jin-Ke Cheng, Li-Shun Wang and Guo-Qiang Chen

in Carcinogenesis

Volume 31, issue 3, pages 419-426
Published in print March 2010 | ISSN: 0143-3334
Published online December 2009 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgp320
Downregulation of ANP32B, a novel substrate of caspase-3, enhances caspase-3 activation and apoptosis induction in myeloid leukemic cells

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The acidic leucine-rich nuclear phosphoprotein 32 (ANP32)B has been reported to regulate gene expression by acting as a histone chaperone or modulate messenger RNA trafficking by serving as a HuR ligand. However, its exact cellular functions are poorly understood. By utilizing a proteomics-based approach, in this work, we identify that the human ANP32B protein is cleaved during apoptosis induction by NSC606985, a novel camptothecin analog. Further investigation shows that various apoptosis inducers cause a decrease of full-length ANP32B in multiple cell lines with a concomitant increase of an ∼17 kDa fragment. The proteolytic cleavage of ANP32B is inhibited by a specific caspase-3 inhibitor Z-DEVD-fmk, and it cannot be seen in NSC606985-induced death of caspase-3-deficient MCF-7 cells. In vitro caspase cleavage assay and mutagenesis experiment reveal that ANP32B is a direct substrate of caspase-3 and it is primarily cleaved at the sequence of Ala-Glu-Val-Asp, after Asp-163. Additionally, the reduced expression of endogenous ANP32B by specific small interfering RNA enhances caspase-3 activation and apoptosis induction by NSC606985 and etoposide. These results suggest that ANP32B is a novel substrate for caspase-3 and acts as a negative regulator for apoptosis, the mechanism of which remains to be explored.

Journal Article.  5929 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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