We examined cAMP response element (CRE)-binding proteins involved in lactate dehydrogenase A (LDHA)-gene transcription in rat liver after partial hepatectomy. Gel retardation and Southwestern blot assays showed that the CRE-binding activity of the 11-16 kDa novel proteins increased in accordance with increases in LDH A-mRNA in regenerating liver tissues, whereas that of the 43 kDa CREB did not. Using CRE-oligonucleotide affinity chromatography and reverse-phase HPLC, we purified four CRE-binding proteins of 11.2, 15.2, 15.8, and 16.3 kDa. N-terminal amino acid sequences of 15.2 and 16.3 kDa proteins revealed a high sequence homology to but were not identical with those of rat histone H2A.1 and H2B, respectively. CRE-bindings of these two proteins were highly specific, while those of histones H2A.1 and H2B were nonspecific as shown by competition-Southwestern blot and DNase I footprinting assays. Taking these data together, we suggest that the novel 11-16 kDa CRE-binding proteins are responsible for the cell growth-dependent inducibility of LDH A-gene transcription during liver regeneration.