Krox-20 inhibits Jun-NH2-terminal kinase/c-Jun to control Schwann cell proliferation and death

Abstract

The transcription factor Krox-20 controls Schwann cell myelination. Schwann cells in Krox-20 null mice fail to myelinate, and unlike myelinating Schwann cells, continue to proliferate and are susceptible to death. We find that enforced Krox-20 expression in Schwann cells cell-autonomously inactivates the proliferative response of Schwann cells to the major axonal mitogen β–neuregulin-1 and the death response to TGFβ or serum deprivation. Even in 3T3 fibroblasts, Krox-20 not only blocks proliferation and death but also activates the myelin genes periaxin and protein zero, showing properties in common with master regulatory genes in other cell types. Significantly, a major function of Krox-20 is to suppress the c-Jun NH2-terminal protein kinase (JNK)–c-Jun pathway, activation of which is required for both proliferation and death. Thus, Krox-20 can coordinately control suppression of mitogenic and death responses. Krox-20 also up-regulates the scaffold protein JNK-interacting protein 1 (JIP-1). We propose this as a possible component of the mechanism by which Krox-20 regulates JNK activity during Schwann cell development.

Thymosin β4 Up-regulation of MicroRNA-146a Promotes Oligodendrocyte Differentiation and Suppression of the Toll-like Proinflammatory Pathway

“…3 and 4). During Schwann cell myelination, a similar opposing effect of MAPKs, p38 MAPK, ERK1, and JNK1, has been reported for the expression of a key tran- scription factor of the MBP promoter, Krox-20, which is also known as EGR2 (early growth response-2) transcription factor (23,26,27). To determine whether T␤4 treatment affected Krox-20 expression in OPCs, we reprobed the Western blots with Krox-20/EGR2 antibodies in OPCs after T␤4 treatment.…”

“…Underlying Signaling Mechanism on the Opposite Effect of Two MAPKs, p38 MAPK and JNK1, on MBP Synthesis-To investigate the underlying signaling mechanism on the effect of p38 MAPK and JNK1 on MBP synthesis, we analyzed the expression of a key transcription factor of the MBP promoter, Krox-20 (26,27,29). Reduction or deficiency of Krox-20/Egr2 in Schwann cells resulted in the failure of MBP synthesis and myelination of axons (30 -32).…”

Identification and Characterization of ZFP-57, a Novel Zinc Finger Transcription Factor in the Mammalian Peripheral Nervous System

“…The plasmid pC-H110 (Amersham Biosciences) carrying the lacZ gene was used in all the transfections. To confirm protein expression of the GAL4 fusion constructs, Western blotting was performed as described previously (20), using an antibody recognizing the GAL4 DNA binding domain (clone 2GV-3, Euromedex.com, Mundolsheim, France).…”

“…These include many myelin protein and lipid genes (19). Krox-20 also has a key role in removing Schwann cells from the cell cycle and in inactivating developmental death signals at the onset of myelination (20). In an in vitro neuron-Schwann cell co-culture system the transcription factor NFB is also required for myelin formation (21).…”

Analysing Microarray Data using the Multi-functional Immune Ontologiser

“…These genes were highly expressed in the tolerant T cells with mRNA expression levels ranging from 24.000 for IRF1 to 38.202 for CCL4. Over-expression of the EGR-2 gene has been associated with the inhibition of T cell activation and promotion of tolerance also known as anergy through many different mechanisms [25,26]. As an example, searching the functions of the EGR-2 gene via the general multi-level GO hierarchy from the Gene Ontology Consortium identified a wide range of biological functions, many of which are not immunology related, such as morphogenesis or organismal physiological processes.…”