Regulation of leukemic cell adhesion, proliferation, and survival by beta-catenin.
In epithelial cells beta-catenin plays a critical role as a component of the cell-cell adhesion apparatus and as a coactivator of the TCF/LEF (T-cell transcription factor/lymphoid enhancer binding factor) family of transcription factors. Deregulation of beta-catenin has been implicated in the malignant transformation of cells of epithelial origin. However, a function for beta-catenin in hematologic malignancies has not been reported. beta-Catenin is not detectable in normal peripheral blood T cells but is expressed in T-acute lymphoblastic leukemia cells and other tumor lines of hematopoietic origin and in primary lymphoid and myeloid leukemia cells. beta-Catenin function was examined in Jurkat T-acute lymphoblastic leukemia cells. Overexpression of dominant-negative beta-catenin or dominant-negative TCF reduced beta-catenin nuclear signaling and inhibited Jurkat proliferation and clonogenicity. Similarly, these constructs inhibited proliferation of K562 and HUT-102 cells. Reduction of beta-catenin expression with beta-catenin antisense down-regulated adhesion of Jurkat cells in response to phytohemagglutinin. Incubation of Jurkat cells with anti-Fas induced caspase-dependent limited proteolysis of beta-catenin N- and C-terminal regions and rapid redistribution of beta-catenin to the detergent-insoluble cytoskeleton, concomitant with a marked decline in nuclear beta-catenin signaling. Fas-mediated apoptosis was potentiated by inhibition of beta-catenin nuclear signaling. The data suggest that beta-catenin can play a significant role in promoting leukemic cell proliferation, adhesion, and survival.
Medical Oncology Clinical Research Unit and Developmental Therapeutics Program, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Eun Joo
EJ
Chung
Sang-Gu
SG
Hwang
PhuongMai
P
Nguyen
Sunmin
S
Lee
Jung-Sik
JS
Kim
Jin Woo
JW
Kim
Pierre A
PA
Henkart
Donald P
DP
Bottaro
Lilian
L
Soon
Paolo
P
Bonvini
Su-Jae
SJ
Lee
Judith E
JE
Karp
Ho Jung
HJ
Oh
Jeffrey S
JS
Rubin
Jane B
JB
Trepel
D017209:Apoptosis; D002448:Cell Adhesion / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003598:Cytoskeletal Proteins / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D003599:Cytoskeleton / Q000378:metabolism; D006801:Humans; D007938:Leukemia / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D008213:Lymphocyte Activation / Q000187:drug effects*; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D015533:Transcriptional Activation / Q000187:drug effects; D014407:Tumor Cells, Cultured; D051176:beta Catenin
C495270:CTNNB1 protein, human; D003598:Cytoskeletal Proteins; D015534:Trans-Activators; D051176:beta Catenin