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29 CCAAT/Enhancer Binding Protein

Steven L. McKnight


In this chapter, I review the biochemical and regulatory properties of CCAAT/enhancer binding protein (C/EBP). The active form of C/EBP is composed of two polypeptide chains held together by short amphipathic α helices. The dimer interface, termed the “leucine zipper,” mimics the intertwining of α helices in coiled-coil proteins such as keratins and lamins. A polypeptide segment immediately amino-terminal to the leucine zipper is rich in basic amino acids. Dimerization brings two such “basic regions” into close apposition, forming a bivalent DNA contact surface. The basic regions are structurally disordered in the absence of DNA but become α helical once bound. At least five distinct C/EBP-related proteins have been described; all bind DNA in a manner similar to C/EBP and can form mixed dimers in vitro. The amino acid sequences of the C/EBP-related proteins are strikingly similar in the basic and leucine zipper regions, yet differ markedly outside the DNA-binding domain. Various lines of evidence have indicated that the originally defined form of C/EBP, now termed C/EBPcα, may play a key role in terminal cell differentiation. Its temporal pattern of expression is tightly correlated to the conversion of 3T3-L1 fibroblasts into nondividing, fat-laden adipocytes. Antisense inhibition of C/EBPα expression blocks adipocyte conversion. Moreover, premature expression of C/EBPα stimulates the terminal differentiation of adipocytes and causes arrest of mitotic growth in a variety of cultured cell types.

Studies on C/EBP began in 1984, when Peter Johnson and Barbara Graves were searching independently for proteins in rat liver nuclear extracts...

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