The human gene (CLP11) encoding p11, the cellular ligand of the tyrosine kinase substrate, annexin II (AnxII), has been isolated from a human genomic library. Restriction mapping and sequencing reveals that CLP11 covers a stretch of approx. 11 kb in the human genome. The structure of CLP11 resembles that of the other genes encoding S-100 proteins which have been characterized so far: the transcribed region is divided by two introns, one in the 5'-nontranslated portion and the second in the protein-coding region. Interestingly, in CLP11, as well as all other S-100 genes, the second intron separates the codons for two corresponding amino acids, which reside in the sequence connecting the two helix-loop-helix (EF-hand) motifs. The 5'-nontranscribed region, which most likely represents the CLP11 promoter, is characterized by a high G+C content and probably is part of a CpG-island. Several putative binding sites for transcription factors can be identified in the 5'-nontranscribed region of CLP11. Among them, the beta DRE element, which was first described in the beta-globin promoter, is most notable, since it is also present in the promoter of ANXII. It could be responsible for the simultaneous induction of CLP11 and ANXII expression during certain cell differentiation processes, e.g., the nerve growth factor-induced differentiation of the pheochromocytoma cell line, PC12.