The Sp1 Family of Transcription Factors Is Involved in p27^Kip1-Mediated Activation of Myelin Basic Protein Gene Expression

Abstract

p27^Kip1 levels increase in many cells as they leave the cell cycle and begin to differentiate. The increase in p27^Kip1 levels generally precedes the expression of differentiation-specific genes. Previous studies from our laboratory showed that the overexpression of p27^Kip1 enhances myelin basic protein (MBP) promoter activity. This activation is specific to p27^Kip1. Additionally, inhibition of cyclin-dependent kinase activity alone is not sufficient to increase MBP expression. In this study, we focused on understanding how p27^Kip1 can activate gene transcription by using the MBP gene in oligodendrocytes as a model. We show that the enhancement of MBP promoter activity by p27^Kip1 is mediated by a proximal region of the MBP promoter that contains a conserved GC box binding sequence. This sequence binds transcription factors Sp1 and Sp3. Increased expression of p27^Kip1 increases the level of Sp1 promoter binding to the GC box but does not change the level of Sp3 binding. The binding of Sp1 to this element activates the MBP promoter. p27^Kip1 leads to increased Sp1 binding through a decrease in Sp1 protein turnover. Enhancement of MBP promoter activity by an increase in the level of p27^Kip1 involves a novel mechanism that is mediated through the stabilization and binding of transcription factor Sp1.

ACKNOWLEDGMENTS

This work was supported by grants from the National Multiple Sclerosis Society (3293-A-5) and the NIH (CA84325).