PHORBOL ESTER-RESISTANT MONOBLASTOID LEUKEMIA-CELLS WITH A FUNCTIONALMITOGEN-ACTIVATED PROTEIN-KINASE CASCADE BUT WITHOUT RESPONSIVE PROTEIN-TYROSINE PHOSPHATASES
H. Seimiya et al., PHORBOL ESTER-RESISTANT MONOBLASTOID LEUKEMIA-CELLS WITH A FUNCTIONALMITOGEN-ACTIVATED PROTEIN-KINASE CASCADE BUT WITHOUT RESPONSIVE PROTEIN-TYROSINE PHOSPHATASES, Oncogene, 11(10), 1995, pp. 2047-2054
Human monoblastoid leukemia U937 cells differentiate to monocyte/macro
phage upon treatment with phorbol ester, 12-O-tetradecanoylphorbol-13-
acetate (TPA). Previous studies, including our own, have demonstrated
that drug-induced differentiation of leukemia cells is associated with
genetic and enzymatic activations of protein tyrosine phosphatases (P
TPases). In this study, to further investigate a relationship between
PTPase activation and leukemic differentiation, we established TPA-res
istant U937 variant UT16 cells. Unlike known TPA-resistant cells whose
resistance is mainly due to lack or down modulation of protein kinase
C (PKC), UT16 cells showed TPA-induced activation of PKC, Raf-1, and
ERK/MAP kinases similar to the parental U937 cells. Interestingly, how
ever, UT16 cells exhibited altered binding activity of AP-1 complexes,
decreased ability to induce c-jun and c-fos gene expressions, and fai
lure to differentiate to a monocytic lineage. Based on these observati
ons, UT16 cells could be considered a novel type of TPA-resistant cell
. Among UT16 cells, most of TPA-inducible PTPase genes, PTP-1C, PTP-ME
G2, P19-PTP, HPTP epsilon, and PTP-U1, did not respond to TPA. Consist
ently, TPA increased PTPase enzymatic activity in U937 but not in UT16
cells. Taken together, activation of PTPases is well correlated with
TPA-induced differentiation of U937 cells. These findings indicate tha
t gene expression and enzymatic activity of some PTPase isozymes descr
ibed here are regulated by a TPA-mediated signaling event and are like
ly to be used as biomarkers for the monocytic differentiation of myelo
id leukemia cells.