p57Kip2 is a downstream effector of BCR-ABL kinase inhibitors in chronic myelogenous leukemia cells.
Chronic myelogenous leukemia (CML) is characterized by the expression of BCR-ABL tyrosine kinase, which results in increased cell proliferation and inhibition of apoptosis. In this study, we show that BCR-ABL-positive CML cell lines treated with imatinib (STI571) undergo G₁ cell cycle arrest associated with the accumulation of p57(Kip)², a cyclin-dependent kinase inhibitor (CKI). Interestingly, p57(Kip)² increase precedes the reported STI571-dependent upregulation of p27(Kip)¹. A number of complementary approaches allow the demonstration that p57(Kip)² buildup is due to the transcriptional activation of CDKN1C, the p57(Kip)²-encoding gene, while neither p57(Kip)² half-life elongation nor its cell relocalization were observed. We also identified a heretofore undescribed pattern of p57(Kip)² phosphorylated isoforms which, however, did not change in response to STI571 cell treatment. The imatinib-dependent p57(Kip)² upregulation occurs only in STI571-responsive cells, while the CKI accumulation was not evidenced in an imatinib-resistant clone. Nilotinib and dasatinib (second-generation BCR-ABL inhibitors), at concentrations comparable to those used in therapy, increase the CKI but do not affect p27(Kip)¹ level. Finally, CD34(+) cells from CML patients display a clear imatinib-dependent p57(Kip)² upregulation, which was not observed in CD34(+) cells from control subjects. In conclusion, our study points to p57(Kip)² as a novel and precocious effector of BCR-ABL targeting drugs.
Department of Biochemistry and Biophysics "Francesco Cedrangolo", Second University of Naples, Italy.
Adriana
A
Borriello
Ilaria
I
Caldarelli
Debora
D
Bencivenga
Valeria
V
Cucciolla
Adriana
A
Oliva
Emilio
E
Usala
Paolo
P
Danise
Luisa
L
Ronzoni
Silverio
S
Perrotta
Fulvio
F
Della Ragione
D000970:Antineoplastic Agents / Q000494:pharmacology; D001549:Benzamides; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D050761:Cyclin-Dependent Kinase Inhibitor p57 / Q000187:drug effects / Q000378:metabolism*; D000069439:Dasatinib; D015180:Electrophoresis, Gel, Two-Dimensional; D016044:Fusion Proteins, bcr-abl / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D000068877:Imatinib Mesylate; D015151:Immunoblotting; D047468:Immunoprecipitation; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000201:enzymology*; D010879:Piperazines / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000187:drug effects / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013844:Thiazoles / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects
D000970:Antineoplastic Agents; D001549:Benzamides; D050761:Cyclin-Dependent Kinase Inhibitor p57; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013844:Thiazoles; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl; C498826:nilotinib; D000069439:Dasatinib