Genetic inactivation of Par4 results in hyperactivation of NF-kappaB and impairment of JNK and p38. Academic Article uri icon

Overview

abstract

  • The Par4 gene was first identified in prostate cells undergoing apoptosis after androgen withdrawal. PAR4 was subsequently shown to interact with, and inhibit, atypical protein kinase C isoforms, functioning as a negative regulator of the NF-kappaB pathway. This may explain its pro-apoptotic function in overexpression experiments. To determine the physiological role of PAR4, we have derived primary embryonic fibroblasts (EFs) from Par4(-/-) mice. We show here that loss of PAR4 leads to a reduction in the ability of tumour necrosis factor-alpha (TNF-alpha) to induce apoptosis by increased activation of NF-kappaB. Consistent with recent reports demonstrating the antagonistic actions of NF-kappaB and c-Jun amino-terminal kinase (JNK) signalling, we have found that Par4(-/-) cells show a reduced activation of the sustained phase of JNK and p38 stimulation by TNF-alpha and interleukin 1. Higher levels of an anti-apoptotic JNK-inhibitor protein, X-chromosome-linked inhibitor of apoptosis, in Par4(-/-) EFs might explain the inhibition of JNK activation in these cells.

publication date

  • March 1, 2003

Research

keywords

  • Mitogen-Activated Protein Kinases
  • NF-kappa B
  • Receptors, Thrombin

Identity

PubMed Central ID

  • PMC1315897

Scopus Document Identifier

  • 0242585506

Digital Object Identifier (DOI)

  • 10.1038/sj.embor.embor769

PubMed ID

  • 12634851

Additional Document Info

volume

  • 4

issue

  • 3