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PML / RARA inhibits expression of HSP 90 and its target AKT
Author(s) -
Piredda Maria Liliana,
Gaur Girish,
Catalano Gianfranco,
Divona Mariadomenica,
Banella Cristina,
Travaglini Serena,
Puzzangara Maria Carmen,
Voso Maria Teresa,
LoCoco Francesco,
Noguera Nelida Ines
Publication year - 2019
Publication title -
british journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.907
H-Index - 186
eISSN - 1365-2141
pISSN - 0007-1048
DOI - 10.1111/bjh.15715
Subject(s) - protein kinase b , retinoic acid , hsp90 , pi3k/akt/mtor pathway , biology , heat shock protein , retinoic acid receptor alpha , microbiology and biotechnology , phosphorylation , acute promyelocytic leukemia , cancer research , chemistry , retinoic acid receptor , signal transduction , biochemistry , gene
Summary Essential for cell survival, the 90 kD Heat Shock Proteins ( HSP 90) are molecular chaperons required for conformational stabilization and trafficking of numerous client proteins. Functional HSP 90 is required for the stability of AKT , a serine‐threonine kinase phosphorylated in response to growth factor stimulation. AKT plays a crucial regulatory role in differentiation, cell cycle, transcription, translation, metabolism and apoptosis. Acute promyelocytic leukaemia ( APL ) is characterized by the presence of the promyelocytic leukaemia/retinoic acid receptor alpha ( PML / RARA ) fusion protein, which deregulates expression of several genes involved in differentiation and apoptosis. Here, we report inhibition of HSP 90 AA 1 and HSP 90 AB 1 isomer transcription in blasts isolated from patients with APL , associated with reduction of HSP 90 protein expression and loss of control on AKT protein phosphorylation. We show that in vitro treatment of PML / RARA expressing cells with all‐ trans retinoic acid ( ATRA ) up‐regulates HSP 90 expression and stabilizes AKT . Addition of the HSP 90‐inhibitor 17‐(allylamino)‐17‐demethoxygeldanamycin in combination with ATRA , blocks upregulation of AKT protein, indicating that HSP 90 is necessary for ATRA action on AKT . This is the first report proving that expression of HSP 90 isomers are directly and differentially repressed by PML / RARA , with critical results on cellular homeostasis of target proteins, such as AKT , in APL blasts.