Studying the Mechanism of Transcriptional Regulation of Mesenchymal Stem Cell Proliferation and Differentiation

Linxia Zhang1, Tim Howes1, Neil Wright2, and Christina Chan1. (1) Chemical Engineering and Material Science, Michigan State University, 2527 Engineering Building, East Lansing, MI 48824, (2) Mechanical Engineering, Michigan State University, 2555 Engineering Building, East Lansing, MI 48824

Mesenchymal stem cells (MSCs) are multipotent adult stem cells which can undergo both self-renewal and multi-lineage differentiation. As an important intracellular second messenger, cAMP has been shown to induce the differentiation of mesenchymal stem cells into neural cells. Elevation of cAMP level is usually tied with the activation of the CREB family proteins, which are important transcription factors involved in proliferation and differentiation. One target gene of the CREB family proteins is cyclin D1. This cell cycle regulator is involved in G1/S phase transition and thus plays a crucial role in proliferation. While activated CREB induces the transcription of cyclin D1, another member of the CREB family protein called ICER inhibits the transcription of cyclin D1 by competing with CREB for binding to the CRE motif. In addition, cyclin D1 has a kB motif in its promoter region, where the transcription factor NF-kB could bind and induce its transcription. NF-kB thereby activates the transcription of cyclin D1 and promotes cell cycle progression. Whether cyclin D1 is up-regulated or down-regulated largely depends on the relative activity of CREB, ICER and NF-kB. Since cyclin D1 is a crucial regulator of G1/S phase transition, its expression may greatly influence cell cycle progression and consequently affect stem cell proliferation versus differentiation.