PMID- 11424089
OWN - NLM
STAT- MEDLINE
DCOM- 20010809
LR  - 20171116
IS  - 0021-9541 (Print)
IS  - 0021-9541 (Linking)
VI  - 188
IP  - 2
DP  - 2001 Aug
TI  - Role of protein kinase Cdelta in transmitting hypoxia signal to HSF and HIF-1.
PG  - 223-35
AB  - An hypoxic microenvironment is an important modulator of gene expression in many 
      pathophysiological conditions. In this study, we show a coordinate activation of 
      heat shock transcription factor (HSF) and hypoxia-inducible factor-1 (HIF-1) in 
      RIF tumor cells by hypoxia. Since heat shock protein (hsp) and angiogenic factor 
      genes that are regulated by HSF and HIF-1 are thought to contribute to the 
      malignant progression of hypoxic tumor cells, it was of our major interest to 
      identify the components that are responsible for the activation of both HSF and 
      HIF-1. Our finding that a bioflavonoid quercetin (QCT), a well known inhibitor of 
      hsp gene expression, significantly inhibited the transcriptional activation of 
      HSF and HIF-1 strongly suggests that QCT-sensitive molecule(s) is involved in the 
      transcriptional activation of HSF and HIF-1 by hypoxia. Our results revealed that 
      PCKalpha, delta and epsilon isoforms are expressed in RIF cells, but only 
      PKCdelta was specifically translocated to the membrane by hypoxia. Our results 
      also revealed that the translocation of PKCdelta was completely abrogated by QCT. 
      Moreover, inhibiting the PKCdelta activation, either pharmacologically with 
      phorbol 12-myristate 13-acetate or with bisindolymaleimide II or genetically by 
      transient transfection of a dominant negative PKCdelta, significantly inhibited 
      the transcriptional activation of HSF and HIF-1 by hypoxia. These results 
      strongly substantiate a view that the PKCdelta isozyme is the QCT-sensitive 
      molecule that plays an important role in transmitting hypoxia signals to both HSF 
      and HIF-1. Here we show that the membrane translocation of PKCdelta is dependent 
      on the activation of phosphoinositol 3-kinase (PI3K). Treatment with PI3K 
      inhibitor, wortmannin or LY294002, abrogated not only PKCdelta translocation but 
      the subsequent transcriptional activation of HSF and HIF-1 by hypoxia. Together, 
      our study shows that the PKCdelta isozyme acts as a shared component in 
      transmitting hypoxia-induced signals to both HSF and HIF-1, and that the upstream 
      regulator of PKCdelta is PI3K.
CI  - Copyright 2001 Wiley-Liss, Inc.
FAU - Baek, S H
AU  - Baek SH
AD  - Department of Biology, University of Incheon, Korea.
FAU - Lee, U Y
AU  - Lee UY
FAU - Park, E M
AU  - Park EM
FAU - Han, M Y
AU  - Han MY
FAU - Lee, Y S
AU  - Lee YS
FAU - Park, Y M
AU  - Park YM
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - J Cell Physiol
JT  - Journal of cellular physiology
JID - 0050222
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (HIF1A protein, human)
RN  - 0 (Heat Shock Transcription Factors)
RN  - 0 (Hypoxia-Inducible Factor 1)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (Isoenzymes)
RN  - 0 (Nuclear Proteins)
RN  - 0 (RNA, Messenger)
RN  - 0 (Transcription Factors)
RN  - 9IKM0I5T1E (Quercetin)
RN  - EC 2.7.1.- (Phosphatidylinositol 3-Kinases)
RN  - EC 2.7.11.13 (PRKCD protein, human)
RN  - EC 2.7.11.13 (Protein Kinase C)
RN  - EC 2.7.11.13 (Protein Kinase C-delta)
SB  - IM
MH  - Cell Hypoxia/physiology
MH  - Cell Membrane/enzymology
MH  - DNA-Binding Proteins/genetics/*metabolism
MH  - *Fibrosarcoma
MH  - Gene Expression Regulation, Enzymologic
MH  - Gene Expression Regulation, Neoplastic
MH  - Heat Shock Transcription Factors
MH  - Humans
MH  - Hypoxia/*metabolism
MH  - Hypoxia-Inducible Factor 1
MH  - Hypoxia-Inducible Factor 1, alpha Subunit
MH  - Isoenzymes/genetics/*metabolism
MH  - Neoplasms, Radiation-Induced
MH  - Nuclear Proteins/genetics/*metabolism
MH  - Phosphatidylinositol 3-Kinases/metabolism
MH  - Protein Kinase C/genetics/*metabolism
MH  - Protein Kinase C-delta
MH  - Quercetin/pharmacology
MH  - RNA, Messenger/analysis
MH  - Signal Transduction/drug effects/*physiology
MH  - *Transcription Factors
MH  - Transcriptional Activation/drug effects/physiology
MH  - Tumor Cells, Cultured
EDAT- 2001/06/26 10:00
MHDA- 2001/08/10 10:01
CRDT- 2001/06/26 10:00
PHST- 2001/06/26 10:00 [pubmed]
PHST- 2001/08/10 10:01 [medline]
PHST- 2001/06/26 10:00 [entrez]
AID - 10.1002/jcp.1117 [pii]
AID - 10.1002/jcp.1117 [doi]
PST - ppublish
SO  - J Cell Physiol. 2001 Aug;188(2):223-35. doi: 10.1002/jcp.1117.