Functional role for protein kinase Cbeta as a regulator of stress-activated protein kinase activation and monocytic differentiation of myeloid leukemia cells.

Abstract:

:Human myeloid leukemia cells respond to 12-O-tetradecanoylphorbol-13-acetate (TPA) and other activators of protein kinase C (PKC) with induction of monocytic differentiation. The present studies demonstrated that treatment of U-937 and HL-60 myeloid leukemia cells with TPA, phorbol-12,13-dibutyrate, or bryostatin 1 was associated with the induction of stress-activated protein kinase (SAPK). In contrast, TPA-resistant TUR and HL-525 cell variants deficient in PKCbeta failed to respond to activators of PKC with the induction of SAPK. A direct role for PKCbeta in TPA-induced SAPK activity in TUR and HL-525 cells that stably express PKCbeta was confirmed. We showed that TPA induced the association of PKCbeta with MEK kinase 1 (MEKK-1), an upstream effector of the SAPK/ERK kinase 1 (SEK1)-->SAPK cascade. The results also demonstrated that PKCbeta phosphorylated and activated MEKK-1 in vitro. The functional role of MEKK-1 in TPA-induced SAPK activity was further supported by the demonstration that the expression of a dominant negative MEKK-1 mutant abrogated this response. These findings indicate that PKCbeta activation is necessary for activation of the MEKK-1-->SEK1-->SAPK cascade in the TPA response of myeloid leukemia cells.

journal_name

Mol Cell Biol

authors

Kaneki M,Kharbanda S,Pandey P,Yoshida K,Takekawa M,Liou JR,Stone R,Kufe D

doi

10.1128/mcb.19.1.461

subject

Has Abstract

pub_date

1999-01-01 00:00:00

pages

461-70

issue

1

eissn

0270-7306

issn

1098-5549

journal_volume

19

pub_type

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