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The Transcriptional Effects of MED1

Aliyah Weinstein, Ph.D.

Sp1 is a transcription factor that can regulate a variety of genes through direct binding to GC-rich areas of DNA and through interactions with other transcription factors including c-myc, c-Jun, and STAT11. Activation of Sp1 requires the activity of CRSP, or cofactor required for Sp1 activation, and one subunit of this protein is MED1, or mediator of RNA polymerase II transcription subunit 12. MED1 is the largest subunit in the CRSP complex and it can also be a part of the more ubiquitous Mediator complex, which activates RNA polymerase II transcription of a wide range of gene targets throughout the genome. Phosphorylation of MED1 appears to support its inclusion in the Mediator complex3. MED1 is furthermore the component of the Mediator complex that targets this complex to nuclear hormone receptors4. MED1 may be referred to by several other names including CRSP1, TRAP220, CRSP200, and PBP.

MED1 regulates transcription downstream of several signaling pathways, including estrogen receptor signaling via interactions with CCAR15, thyroid hormone receptor, and the vitamin D receptor6. Phosphorylation of MED1 by ERK appears to augment the downstream effects of signaling through the thyroid hormone receptor7 and the vitamin D receptor8. Activation of Sp1 requires interaction between CRSP and transcription factors of the TFII family, notably TFIID. While Sp1 is a transcriptional enhancer, CRSP and TFIID form the transcription factor complex necessary to recruit Sp1 to the gene site2,9.

The transcriptional effects of MED1 play a key part in many different cell types and organ systems throughout the body. MED1-mediated transcription in bone marrow stromal cells helps to maintain hematopoietic stem cells in that niche by regulating the expression of osteopontin downstream of vitamin D receptor signaling10. MED1 is also expressed by keratinocytes in the skin, where it promotes the maintenance of hair growth11. MED1 has been reported to play diverse roles in cancer progression. In non-small cell lung cancer, loss of MED1 promotes cancer metastasis12 and in invasive bladder cancer, MED1 expression was reported to be decreased and low MED1 expression was associated with decreased survival13. A similar effect was observed in melanoma, where low levels of expression of MED1 was associated with an invasive phenotype14. In breast cancer, MED1 functions in crosstalk between the estrogen and HER2 receptors, and MED1 expression promotes resistance to tamoxifen therapy15. MED1 also plays a role in regulating metabolism, and loss of MED1 promoted mitochondrial biogenesis and a shift towards oxidative phosphorylation16. Thus, transcription mediated by MED1 complexes plays diverse roles in organ systems throughout the body and has different effects depending on the upstream signaling pathway and cell type controlling its expression.

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References

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