Notch/HES1-mediated PARP1 activation: a cell type-specific mechanism for tumor suppression.
Blood
; 117(10): 2891-900, 2011 Mar 10.
Article
in En
| MEDLINE
| ID: mdl-21224467
ABSTRACT
Notch signaling plays both oncogenic and tumor suppressor roles, depending on cell type. In contrast to T-cell acute lymphoblastic leukemia (ALL), where Notch activation promotes leukemogenesis, induction of Notch signaling in B-cell ALL (B-ALL) leads to growth arrest and apoptosis. The Notch target Hairy/Enhancer of Split1 (HES1) is sufficient to reproduce this tumor suppressor phenotype in B-ALL; however, the mechanism is not yet known. We report that HES1 regulates proapoptotic signals by the novel interacting protein Poly ADP-Ribose Polymerase1 (PARP1) in a cell type-specific manner. Interaction of HES1 with PARP1 inhibits HES1 function, induces PARP1 activation, and results in PARP1 cleavage in B-ALL. HES1-induced PARP1 activation leads to self-ADP ribosylation of PARP1, consumption of nicotinamide adenine dinucleotide(+), diminished adenosine triphosphate levels, and translocation of apoptosis-inducing factor from mitochondria to the nucleus, resulting in apoptosis in B-ALL but not T-cell ALL. Importantly, induction of Notch signaling by the Notch agonist peptide Delta/Serrate/Lag-2 can reproduce these events and leads to B-ALL apoptosis. The novel interaction of HES1 and PARP1 in B-ALL modulates the function of the HES1 transcriptional complex and signals through PARP1 to induce apoptosis. This mechanism shows a cell type-specific proapoptotic pathway that may lead to Notch agonist-based cancer therapeutics.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Precursor B-Cell Lymphoblastic Leukemia-Lymphoma
/
Poly(ADP-ribose) Polymerases
/
Homeodomain Proteins
/
Enzyme Activation
/
Basic Helix-Loop-Helix Transcription Factors
/
Receptors, Notch
Limits:
Child
/
Humans
Language:
En
Journal:
Blood
Year:
2011
Document type:
Article
Affiliation country:
United States