TY - JOUR
T1 - Mitochondrial pro-apoptotic ARTS protein is lost in the majority of acute lymphoblastic leukemia patients
AU - Elhasid, Ronit
AU - Sahar, Dvora
AU - Merling, Ayellet
AU - Zivony, Yifat
AU - Rotem, Asaf
AU - Ben-Arush, Miriam
AU - Izraeli, Shai
AU - Bercovich, Dani
AU - Larisch, Sarit
N1 - Funding Information:
We wish to thank Hermann Steller for his help throughout this work and for thoughtful reading of the manuscript. We also thank Ziva Weissman for excellent technical assistance, Zvi Ben-Ishai from Rambam Medical Center, Haifa, Israel for his continuous support, David Barzilai and the Erna D Leir Foundation for Research of Degenerative Brain Diseases for their generous support. This work was supported by a grant from the Israel Cancer Association and a grant from the Israel Science Foundation.
PY - 2004/7/15
Y1 - 2004/7/15
N2 - Acquired resistance towards apoptosis is the hallmark of most if not all types of cancer. We have previously identified and characterized ARTS, a broadly expressed protein localized to mitochondria. ARTS was initially shown to mediate TGF-β induced apoptosis. Recently, we have found that high levels of ARTS induce apoptosis without additional pro-apoptotic stimuli. Further, ARTS promotes apoptosis in response to a wide variety of proapoptotic stimuli. Here, we report that the expression of ARTS is lost in all lymphoblasts of more than 70% of childhood acute lymphoblastic leukemia (ALL) patients. The loss of ARTS is specific, as the related non-apoptotic protein H5, bearing 83% identity to ARTS, is unaffected. During remission, ARTS expression is detected again in almost all patients. Two leukemic cell lines, ALL-1 and HL-60 lacking ARTS, were resistant to apoptotic induction by ara-C. Transfection of ARTS into these cells restored their ability to undergo apoptosis in response to this chemotherapeutic agent. We found that methylation process contributes to the loss of ARTS expression. We conclude that the loss of ARTS may provide a selective advantage for cells to escape apoptosis thereby contributing to their transformation to malignant lymphoblasts. We therefore propose that ARTS can fraction as a tumor suppressor protein in childhood ALL.
AB - Acquired resistance towards apoptosis is the hallmark of most if not all types of cancer. We have previously identified and characterized ARTS, a broadly expressed protein localized to mitochondria. ARTS was initially shown to mediate TGF-β induced apoptosis. Recently, we have found that high levels of ARTS induce apoptosis without additional pro-apoptotic stimuli. Further, ARTS promotes apoptosis in response to a wide variety of proapoptotic stimuli. Here, we report that the expression of ARTS is lost in all lymphoblasts of more than 70% of childhood acute lymphoblastic leukemia (ALL) patients. The loss of ARTS is specific, as the related non-apoptotic protein H5, bearing 83% identity to ARTS, is unaffected. During remission, ARTS expression is detected again in almost all patients. Two leukemic cell lines, ALL-1 and HL-60 lacking ARTS, were resistant to apoptotic induction by ara-C. Transfection of ARTS into these cells restored their ability to undergo apoptosis in response to this chemotherapeutic agent. We found that methylation process contributes to the loss of ARTS expression. We conclude that the loss of ARTS may provide a selective advantage for cells to escape apoptosis thereby contributing to their transformation to malignant lymphoblasts. We therefore propose that ARTS can fraction as a tumor suppressor protein in childhood ALL.
KW - ARTS
KW - Apoptosis
KW - Leukemia
KW - Mitochandria
UR - http://www.scopus.com/inward/record.url?scp=3843059163&partnerID=8YFLogxK
U2 - 10.1038/sj.onc.1207725
DO - 10.1038/sj.onc.1207725
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C2 - 15122323
AN - SCOPUS:3843059163
SN - 0950-9232
VL - 23
SP - 5468
EP - 5475
JO - Oncogene
JF - Oncogene
IS - 32
ER -