Post-Transcriptional Regulation of MKK4-A Stress Signaling Kinase Implicated in the Regulation of Metastatic Growth
Abstract
Mitogen-activated protein kinase kinase 4 (MKK4) is a dual-specificity kinase with a critical role in regulating the activity of the c-Jun-N-terminal kinase (JNK) and p38 kinases. We identified a novel biological function for MKK4 in the regulation of growth of ovarian and prostate cancer metastases. Previous clinical correlative studies showed that MKK4 protein levels were reduced in high-grade prostate cancer and prostate and ovarian cancer metastases as compared to normal tissue controls. These findings prompted the investigation of mechanism(s) responsible for down-regulation of MKK4 in a panel of cancer cell lines. Initial studies found that low levels of MKK4 protein did not correlate with either exon deletion or decreased levels of MKK4 mRNA, suggesting that MKK4 protein levels were regulated by either reduced translation or reduced protein stability. The endogenous MKK4 protein was very stable and did not appear to be subject to altered proteolysis. Instead, MKK4 biosynthesis appeared may be regulated by altered translation. In support of this assertion, we found that the cytosolic MKK4 mRNA was shifted towards active polysomes in cells with higher levels of MKK4 protein, suggesting that MKK4 mRNA was translated more efficiently in these cells. This study supports a novel mechanism for the regulation of MKK4 protein levels. Further, these findings have potential therapeutic implications for modulating the expression of an important signaling kinase involved in the regulation of metastatic growth.
Document Details
- Document Type
- Technical Report
- Publication Date
- Apr 01, 2006
- Accession Number
- ADA457439
Entities
People
- Carrie W. Rinker-schaeffer
Organizations
- University of Chicago