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First published online June 8, 2005
doi: 10.1242/10.1242/jcs.02459

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Molecular stop signs: regulation of cell-cycle arrest by C/EBP transcription factors

Laboratory of Protein Dynamics and Signaling, Center for Cancer Research, NCI-Frederick, Frederick, MD 21702-1201, USA

View larger version (25K): [in a new window]   Fig. 1. (A) Domain organization of C/EBP-family members. Each C/EBP protein contains a functionally related leucine zipper dimerization domain (LZ) at its C-terminus. All family members, with the exception of C/EBP, share an adjacent highly conserved basic region (BR) that mediates sequence-specific DNA binding. C/EBP, C/EBPß, C/EBP and C/EBP each contain transactivation domains (TADs) and a regulatory domain (RD) located in their N-terminal regions. A tripartite TAD at the N-terminus displays homology among several of the family members (Williams et al., 1995). (B) The predicted structure of a C/EBP bZIP dimer bound to its cognate DNA site.

View larger version (7K): [in a new window]   Fig. 2. C/EBP functional domains, protein interaction regions and phosphorylation sites. The two major translational isoforms, p42 and p30, are shown. Three distinct transactivation elements (TE-I, TE-II and TE-III) have been identified (Friedman and McKnight, 1990; Nerlov and Ziff, 1994). Sequences mediating binding to various effector proteins regulating cell-cycle arrest are indicated; brackets denote regions whose boundaries are only approximately known. Two different CDK interaction regions have been reported (see text). Functionally relevant phosphoacceptor sites are depicted in blue.

View larger version (42K): [in a new window]   Fig. 3. Models of C/EBP-induced cell-cycle arrest. The figure shows key events regulating G1-S progression during the mitotic cycle. Activation of CDK4/CDK6 and, later, CDK2 by induction of cyclins leads to phosphorylation of pRB and its release from E2F transcription factors. CDK inhibitors such as p21 can block this step. Dissociation of phosphorylated pRB relieves repression of S-phase genes, which are otherwise inhibited by pRB-E2F through recruitment of the SWI/SNF chromatin-remodeling complex and histone deacetylases (not shown). The models of C/EBP action fall into two categories: direct or p21-dependent inhibition of CDK activity (non-transcriptional) and repression of S-phase genes (transcriptional). C/EBP may be tethered to target S-phase gene promoters indirectly by E2F or it could bind directly to E2F sites. Alternatively, S-phase genes might contain C/EBP-binding sites in their promoters (not shown).

View larger version (23K): [in a new window]   Fig. 4. C/EBP basic region residues involved in protein-DNA interaction. Shown are important DNA base contacts and side chain interactions determined from the crystal structure. The sequence of the C/EBP basic region and the palindromic consensus C/EBP site (blue lettering) are also depicted. Figure adapted from Miller et al. (Miller et al., 2003).