MED28, a mammalian Mediator subunit, exhibits several cellular roles, including a merlin, Grb2, and cytoskeleton-associated protein (magicin), a repressor of smooth muscle cell differentiation, and an endothelial-derived gene (EG-1). Overexpression of MED28 may stimulate cell proliferation which presumably results from the transcriptional activation of the Mediator function. Additionally, several tumors, including breast cancer, highly express MED28. We have found recently that MED28 potentiated epidermal growth factor (EGF)-induced migration in human breast cancer cells. Therefore, the objective of this study is to identify the role of MED28 in the aspect of cellular migration and invasion in human breast cancer cells. Suppression of MED28 blocked cellular migration and invasion with concomitant reduced expression levels of matrix metalloproteinase-2 (MMP2) and mitogen-activated protein kinase kinase 1 (MAP2K1; MEK1); overexpression of MED28 enhanced cellular migration and upregulated MMP2 and MEK1 expression. Moreover, suppression of MEK1, by dominant-negative, kinase-dead MEK1 cDNA construct or MEK1-specific small interfering RNA (siRNA) as well as MEK1 inhibitors, blocked MED28-induced MMP2 activation, cellular migration, and invasion in breast cancer cells. Furthermore, ectopic expression of MEK1 rescued the inhibitory effect of MED28 knockdown on invasion, and exogenous MMP2 recombinant protein recovered the suppression on invasion upon MED28 or MEK1 knockdown. Our data indicate that MED28 regulates cellular migration in a MEK1-dependent manner in human breast cancer cells, reinforcing the important cellular roles of MED28.
MED28 exhibits multiple cellular roles, including involved in transcriptional activation and as a merlin, Grb2, and cytoskeleton‐associated protein, which is highly expressed in several types of tumor. Recently, we have reported that MED28 regulates cellular migration and invasion in human breast cancer cells. Furthermore, overexpression of MED28 stimulates cell proliferation; however, the principal mechanism remains unclear. Therefore, the objective of this study is to understand the role of MED28 in the aspect of cell growth in breast cancer cells. MED28 suppression delays cell cycle progression in human breast cancer cells. MED28 appears to modulate cell growth through HMG box‐containing protein 1 (HBP1), a tumor suppressor which down‐regulates genes in G1 to S transition, and whose mutation or reduction is often manifested in invasive breast cancer. Overexpression of MED28 enhances cell cycle progression and downregulates HBP1 expression, whereas HBP1 cDNA partially blocks the stimulatory effect of MED28 on cell growth. Our data indicate that MED28 promotes cell cycle progression and stimulates cell proliferation, reinforcing the significance of MED28 in breast cancer development. (This work was supported by the grants, NSC 98–2320‐B‐309–002‐MY3 and NSC101–2320‐B‐309–001 to M‐F Lee, and CMU95–311 to C‐Y Huang.)
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