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Stress pathway activation induces phosphorylation of retinoid X receptor
H Y Lee1, Y A Suh, M J Robinson
1Department of Thoracic/Head and Neck Medical Oncology, Clinical Cancer Prevention, University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
Abstract:
Cellular stresses inhibit retinoid signaling, but the molecular basis for this phenomenon has not been revealed. Here, we present evidence that retinoid X receptor (RXR) is a substrate for both mitogen-activated protein kinase kinase-4 (MKK4/SEK1) and its downstream mediator c-Jun N-terminal kinase (JNK). MKK4/SEK1 and JNK recognized distinct features on RXR in the DE and AB regions, respectively. Phosphorylation by MKK4/SEK1 had profound effects on the biochemical properties of RXR, inhibiting the expression of genes activated by RXR-retinoic acid receptor complexes. Tyr-249 in the RXR DE region was required for the inhibitory effect of MKK4/SEK1. These effects were significantly reduced in MKK4/SEK1-null cells, indicating that MKK4/SEK1 is required for the suppression of retinoid signaling by stress. Findings presented here demonstrate that MKK4/SEK1 can directly modulate transcription by phosphorylating RXR, a novel MKK4/SEK1 substrate.
Insights
Cellular stress suppresses retinoid signaling by phosphorylating the retinoid X receptor (RXR). Mitogen-activated protein kinase kinase-4 (MKK4/SEK1) directly inhibits gene expression by modifying RXR.
Area of Science:
- Molecular Biology
- Cellular Signaling
- Transcription Regulation
Background:
- Cellular stresses are known to inhibit retinoid signaling pathways.
- The precise molecular mechanisms underlying this inhibition have remained largely unelucidated.
Purpose of the Study:
- To investigate the molecular basis by which cellular stresses inhibit retinoid signaling.
- To identify key proteins involved in the stress-induced suppression of retinoid receptor activity.
Main Methods:
- Investigated retinoid X receptor (RXR) as a potential substrate for stress-activated kinases.
- Utilized MKK4/SEK1-null cells to assess the role of MKK4/SEK1 in retinoid signaling suppression.
- Examined the effects of MKK4/SEK1 phosphorylation on RXR's transcriptional activity.
Main Results:
- Retinoid X receptor (RXR) is a direct substrate for mitogen-activated protein kinase kinase-4 (MKK4/SEK1) and c-Jun N-terminal kinase (JNK).
- MKK4/SEK1 phosphorylation of RXR inhibits the expression of retinoid-activated genes, with Tyr-249 being crucial for this effect.
- MKK4/SEK1 is essential for stress-induced suppression of retinoid signaling, as evidenced by reduced effects in MKK4/SEK1-null cells.
Conclusions:
- Mitogen-activated protein kinase kinase-4 (MKK4/SEK1) directly modulates transcription by phosphorylating retinoid X receptor (RXR).
- This study identifies RXR as a novel substrate for MKK4/SEK1, revealing a new regulatory mechanism in retinoid signaling under cellular stress.