TY  - JOUR
A1  - Weber, Axel
A1  - Borghouts, Corina
A1  - Brendel, Christian
A1  - Moriggl, Richard
A1  - Delis, Natalia
A1  - Brill, Boris
A1  - Vafaizadeh, Vida
A1  - Groner, Bernd
T1  - Stat5 exerts distinct, vital functions in the cytoplasm and nucleus of Bcr-Abl+ K562 and Jak2(V617F)+ HEL leukemia cells
T2  - Cancers
N2  - Signal transducers and activators of transcription (Stats) play central roles in the conversion of extracellular signals, e.g., cytokines, hormones and growth factors, into tissue and cell type specific gene expression patterns. In normal cells, their signaling potential is strictly limited in extent and duration. The persistent activation of Stat3 or Stat5 is found in many human tumor cells and contributes to their growth and survival. Stat5 activation plays a pivotal role in nearly all hematological malignancies and occurs downstream of oncogenic kinases, e.g., Bcr-Abl in chronic myeloid leukemias (CML) and Jak2(V617F) in other myeloproliferative diseases (MPD). We defined the mechanisms through which Stat5 affects growth and survival of K562 cells, representative of Bcr-Abl positive CML, and HEL cells, representative for Jak2(V617F) positive acute erythroid leukemia. In our experiments we suppressed the protein expression levels of Stat5a and Stat5b through shRNA mediated downregulation and demonstrated the dependence of cell survival on the presence of Stat5. Alternatively, we interfered with the functional capacities of the Stat5 protein through the interaction with a Stat5 specific peptide ligand. This ligand is a Stat5 specific peptide aptamer construct which comprises a 12mer peptide integrated into a modified thioredoxin scaffold, S5-DBD-PA. The peptide sequence specifically recognizes the DNA binding domain (DBD) of Stat5. Complex formation of S5-DBD-PA with Stat5 causes a strong reduction of P-Stat5 in the nuclear fraction of Bcr-Abl-transformed K562 cells and a suppression of Stat5 target genes. Distinct Stat5 mediated survival mechanisms were detected in K562 and Jak2(V617F)-transformed HEL cells. Stat5 is activated in the nuclear and cytosolic compartments of K562 cells and the S5-DBD-PA inhibitor most likely affects the viability of Bcr-Abl+ K562 cells through the inhibition of canonical Stat5 induced target gene transcription. In HEL cells, Stat5 is predominantly present in the cytoplasm and the survival of the Jak2(V617F)+ HEL cells is impeded through the inhibition of the cytoplasmic functions of Stat5.
KW  - peptide aptamer (PA)
KW  - signal transducer and activator of transcription 5 (Stat5)
KW  - RNA interference (RNAi)
KW  - protein/lentiviral transduction
KW  - chronic myeloid leukemia (CML)
KW  - human erythroid leukemia (HEL)
KW  - Bcr-Abl
KW  - Jak2(V617F)
KW  - canonical/non-canonical
Y1  - 2015
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/54335
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-543358
SN  - 2072-6694
N1  - This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
VL  - 7
IS  - 1
SP  - 503
EP  - 537
PB  - MDPI
CY  - Basel
ER  -