Prostate apoptosis response gene-4 (par-4) abrogates the survival function of p185(BCR-ABL) in hematopoietic cells.
OBJECTIVE
Prostate apoptosis response gene-4 (par-4) is deregulated in acute and chronic lymphatic leukemia. Given its pro-apoptotic role in neoplastic lymphocytes and evidence that par-4 antagonizes oncogenic Ras in solid tumors, we hypothesized that par-4 may act as a tumor suppressor impairing transformation induced by p185(BCR-ABL).


METHODS
The capacity of par-4 to interfere with factor independence induced by p185(BCR-ABL) and V12ras was evaluated by analysis of factor-independent growth of p185(BCR-ABL)/ par-4 and V12ras/par-4 transduced cells. The expression of par-4 and p185(BCR-ABL) by the respective constructs was controlled by Western blot analysis. Activated Ras was detected by pull-down assay in the cell clones expressing p185(BCR-ABL) in the absence and presence of par-4.


RESULTS
Expression of p185(BCR-ABL) causes factor independence, signifying a conversion toward a transformed phenotype in hematopoietic precursors. We demonstrate that par-4 completely abolishes factor independence induced by p185(BCR-ABL) and partially abrogates factor independence caused by activated V12ras. Evaluating the underlying molecular mechanisms, we show that par-4 hinders activation of oncogenic Ras and causes concomitant disruptions of p185(BCR-ABL)-mediated signaling.


CONCLUSIONS
We provide the first evidence that par-4 exhibits an antitransforming capacity by antagonizing p185(BCR-ABL)-induced factor-independent proliferation in hematopoietic cells.
Kukoc-Zivojnov
Natasa
N
Department of Medicine III, Johann Wolfgang Goethe-University Hospital, Frankfurt, Germany.
Puccetti
Elena
E
Chow
Kai U
KU
Bergmann
Marion
M
Ruthardt
Martin
M
Hoelzer
Dieter
D
Mitrou
Paris S
PS
Weidmann
Eckhart
E
Boehrer
Simone
S
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics*; D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins / Q000235:genetics*; D002455:Cell Division / Q000502:physiology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics; D003001:Cloning, Molecular; D003114:Colony-Forming Units Assay; D016044:Fusion Proteins, bcr-abl / Q000235:genetics; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000473:pathology; D006801:Humans; D007377:Interleukin-3 / Q000037:antagonists & inhibitors / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics; D008297:Male; D051379:Mice; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics; D011467:Prostate; D051381:Rats; D014162:Transfection
D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins; D007377:Interleukin-3; D047908:Intracellular Signaling Peptides and Proteins; C101296:prostate apoptosis response-4 protein; D016044:Fusion Proteins, bcr-abl