Abstract
Essential for cell survival, the 90 kD Heat Shock Proteins (HSP90) are molecular chaperons required for conformational stabilization and trafficking of numerous client proteins. Functional HSP90 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 HSP90AA1 and HSP90AB1 isomer transcription in blasts isolated from patients with APL, associated with reduction of HSP90 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 HSP90 expression and stabilizes AKT. Addition of the HSP90-inhibitor 17-(allylamino)-17-demethoxygeldanamycin in combination with ATRA, blocks upregulation of AKT protein, indicating that HSP90 is necessary for ATRA action on AKT. This is the first report proving that expression of HSP90 isomers are directly and differentially repressed by PML/RARA, with critical results on cellular homeostasis of target proteins, such as AKT, in APL blasts.
| Original language | English |
|---|---|
| Journal | British Journal of Haematology |
| DOIs | |
| Publication status | Accepted/In press - Jan 1 2018 |
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Keywords
- Acute promyelocytic leukaemia
- AKT
- heat shock protein 90
- HSP90AA1 and HSP90AB1
- PML/RARA
ASJC Scopus subject areas
- Hematology
Cite this
PML/RARA inhibits expression of HSP90 and its target AKT. / Piredda, Maria Liliana; Gaur, Girish; Catalano, Gianfranco; Divona, Mariadomenica; Banella, Cristina; Travaglini, Serena; Puzzangara, Maria Carmen; Voso, Maria Teresa; Lo-Coco, Francesco; Noguera, Nelida Ines.
In: British Journal of Haematology, 01.01.2018.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - PML/RARA inhibits expression of HSP90 and its target AKT
AU - Piredda, Maria Liliana
AU - Gaur, Girish
AU - Catalano, Gianfranco
AU - Divona, Mariadomenica
AU - Banella, Cristina
AU - Travaglini, Serena
AU - Puzzangara, Maria Carmen
AU - Voso, Maria Teresa
AU - Lo-Coco, Francesco
AU - Noguera, Nelida Ines
PY - 2018/1/1
Y1 - 2018/1/1
N2 - Essential for cell survival, the 90 kD Heat Shock Proteins (HSP90) are molecular chaperons required for conformational stabilization and trafficking of numerous client proteins. Functional HSP90 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 HSP90AA1 and HSP90AB1 isomer transcription in blasts isolated from patients with APL, associated with reduction of HSP90 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 HSP90 expression and stabilizes AKT. Addition of the HSP90-inhibitor 17-(allylamino)-17-demethoxygeldanamycin in combination with ATRA, blocks upregulation of AKT protein, indicating that HSP90 is necessary for ATRA action on AKT. This is the first report proving that expression of HSP90 isomers are directly and differentially repressed by PML/RARA, with critical results on cellular homeostasis of target proteins, such as AKT, in APL blasts.
AB - Essential for cell survival, the 90 kD Heat Shock Proteins (HSP90) are molecular chaperons required for conformational stabilization and trafficking of numerous client proteins. Functional HSP90 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 HSP90AA1 and HSP90AB1 isomer transcription in blasts isolated from patients with APL, associated with reduction of HSP90 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 HSP90 expression and stabilizes AKT. Addition of the HSP90-inhibitor 17-(allylamino)-17-demethoxygeldanamycin in combination with ATRA, blocks upregulation of AKT protein, indicating that HSP90 is necessary for ATRA action on AKT. This is the first report proving that expression of HSP90 isomers are directly and differentially repressed by PML/RARA, with critical results on cellular homeostasis of target proteins, such as AKT, in APL blasts.
KW - Acute promyelocytic leukaemia
KW - AKT
KW - heat shock protein 90
KW - HSP90AA1 and HSP90AB1
KW - PML/RARA
UR - http://www.scopus.com/inward/record.url?scp=85058085304&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85058085304&partnerID=8YFLogxK
U2 - 10.1111/bjh.15715
DO - 10.1111/bjh.15715
M3 - Article
AN - SCOPUS:85058085304
JO - British Journal of Haematology
JF - British Journal of Haematology
SN - 0007-1048
ER -