title: PRAM-1 potentiates arsenic trioxide-induced JNK activation.
abstract: The promyelocytic leukemia RARalpha target gene encoding an adaptor molecule-1 (PRAM-1) is involved in a signaling pathway induced by retinoic acid in acute promyelocytic leukemia (APL) cells. To better understand the function of PRAM-1, we have undertaken the identification of its partners through a yeast two-hybrid screen. Here, we show that the proline-rich domain of PRAM-1 interacted with the Src homology 3 (SH3) domain of hematopoietic progenitor kinase 1 (HPK-1)-interacting protein of 55 kDa (HIP-55, also called SH3P7 and Abp1) known to stimulate the activity of HPK-1 and c-Jun N-terminal kinase (JNK). Overexpression of PRAM-1 in the NB4 APL cell line increased arsenic trioxide-induced JNK activation through a caspase 3-like-dependent activity. Dissociation of the SH3 domain from the rest of the HIP-55 protein was observed in the NB4 APL cell line treated with arsenic trioxide due to specific cleavage by caspase 3-like enzymes. The cleavage of HIP-55 correlated with the induction of PRAM-1 mRNA and protein expression. Taken together, our results suggest that the caspase 3-cleaved SH3 domain of HIP-55 is likely involved in PRAM-1-mediated JNK activation upon arsenic trioxide-induced differentiation of NB4 cells.
authors.affiliation: Hôpital Robert Debré, INSERM U417, 48 Boulevard Serurier, F-75935 Paris, Cedex 19, France.
authors.forename: Frédéric M
authors.initials: FM
authors.lastname: Denis
authors.forename: Arndt
authors.initials: A
authors.lastname: Benecke
authors.forename: Yolande
authors.initials: Y
authors.lastname: Di Gioia
authors.forename: Ivo P
authors.initials: IP
authors.lastname: Touw
authors.forename: Yvon E
authors.initials: YE
authors.lastname: Cayre
authors.forename: Pierre G
authors.initials: PG
authors.lastname: Lutz
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004789:Enzyme Activation; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D007700:Kinetics; D015473:Leukemia, Promyelocytic, Acute; D008840:Microfilament Proteins / Q000378:metabolism; D009842:Oligopeptides / Q000494:pharmacology; D010087:Oxides / Q000494:pharmacology*; D011506:Proteins / Q000378:metabolism*; D014212:Tretinoin / Q000494:pharmacology; D018909:src Homology Domains
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D001152:Arsenicals; D015853:Cysteine Proteinase Inhibitors; C117063:DBNL protein, human; D008840:Microfilament Proteins; D009842:Oligopeptides; D010087:Oxides; C430907:PRAM1 protein, human; D011506:Proteins; C110772:benzoylcarbonyl-aspartyl-glutamyl-valyl-aspartyl-fluoromethyl ketone; D014212:Tretinoin; D048031:JNK Mitogen-Activated Protein Kinases; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D000077237:Arsenic Trioxide