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The Apoptosis Related BIM Is An HSP70‐Specific Client Protein
Author(s) -
Rodina Anna,
Kang Yanlong,
Taldone Tony,
Patel Pallav,
Patel Hardik,
Chiosis Gabriela
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.955.6
Subject(s) - hsp70 , apoptosis , inhibitor of apoptosis , proteases , microbiology and biotechnology , heat shock protein , chaperone (clinical) , hsp90 , caspase , regulator , hsp90 inhibitor , proteasome , cleavage (geology) , biology , chemistry , cancer research , programmed cell death , biochemistry , enzyme , medicine , pathology , gene , paleontology , fracture (geology)
Heat shock protein chaperones have important roles in regulating the function of cells under pathogenic stress, including cancer. Among them, heat inducible Hsp70 and constitutive Hsc70 are of especial interest because they act upstream of the major onco‐protein regulator chaperone, Hsp90, and additionally, they have potent anti‐apoptotic activities by inhibiting both intrinsic and extrinsic death pathways. Here we use a novel Hsp70/Hsc70 inhibitor, YK5, to study a mechanism of Hsp70‐dependent apoptosis in breast cancer cells. We show that the Hsp70 inhibitor activates caspase 8 – depended apoptotic pathways and induces cleavage of the apoptotic protein Bim. We show through chemical precipitation that Bim physically associates with the Hsp70 protein, demonstrating that it is an Hsp70 client protein. Following Hsp70 inhibitor treatment, we identify the formation of a cleaved Bim product, a Bim‐species previously demonstrated to be more efficient at inducing apoptosis than the full‐length protein. Proteasome and serine proteases are involved in Hsp70 – depended Bim degradation and cleavage, and inhibition of serine proteases correlates with a decrease in the Hsp70 inhibitor – induces apoptosis. The data suggest Bim to be an important player in Hsp70 ‐ regulated apoptosis inhibition in cancer cells, and indicate Hsp70 as a potential inhibitor of the formation of the hyperactive cleaved Bim species.