Oct-1 transcription factor has various functions in gene regulation. Its expression level is increased in several types of cancer and is associated with poor survival prognosis. Here we identified distinct Oct-1 protein isoforms in human cells and compared gene expression patterns and functions for Oct-1A, Oct-1L, and Oct-1X isoforms that differ by their N-terminal sequences. The longest isoform, Oct-1A, is abundantly expressed and is the main Oct-1 isoform in most of human tissues. The Oct-1L and the weakly expressed Oct-1X regulate the majority of Oct-1A targets as well as additional sets of genes. Oct-1X controls genes involved in DNA replication, DNA repair, RNA processing, and cellular response to stress. The high level of Oct-1 isoforms upregulates genes related to cell cycle progression and activates proliferation both in Namalwa Burkitt's lymphoma cells and primary human fibroblasts. It downregulates expression of genes related to antigen processing and presentation, cytokine-cytokine receptor interaction, oxidative metabolism, and cell adhesion, thus facilitating pro-oncogenic processes.

The 5P-upstream region (1.3 kb) of the gene encoding the POU domain transcription factor Oct-1 was cloned and sequenced. CAT reporter gene analysis of this region has detected a functionally active promoter. This region contains 24 TAAT-core sites, arranged in five clusters (four to six sites in one cluster) ; two octamer sites (ATGCAAAT) are located in the first and second clusters; in the second one the CCAAT-box adjacent to the octamer overlaps with the TAAT-core site. As shown by gel retardation assay, Oct-1, Oct-2, and some unknown proteins from myeloma cell line NS/0 interact with the TAATcore sites of these clusters. The results suggest autoregulation of Oct-1 gene expression that may also be controlled by other POU proteins, homeodomain proteins and CCAAT trans-action factors.z 1998 Federation of European Biochemical Societies.

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The best target of POU proteins (Oct-1, Oct-2) is an octamer sequence ATGCAAAT. POU proteins also recognize, with weaker affinity, the TAAT-like targets of another group of regulatory factors, the homeoproteins. Up to now, it has not been known why Cys50 of the POUHdomain is absolutely conserved in contrast to that in homeoproteins. To assess the importance of Cys50 in determining the binding specificity of POU proteins, all possible amino acids were substituted for Cys at position 50, and the resulting mutants were tested with probes containing octamer (ATGCAAATNN) or homeospecific binding sites. Only the wild-type POU was shown to adequately discriminate between the octamer and homeospecific sites, and the protein affinity was only slightly affected by the nucleotide sequence flanking the octamer at the 3'-end. Any amino acid substitution at position 50 resulted in the mutant protein binding efficiently both to the octamer and the TAAT-like sequences. Moreover, in this case the 3'-flanking sequences influenced the binding to a much greater extent.

Oct-1(POU2F1) is a DNA-binding transcription regulator and its level being highly increased in many human cancers. Oct-1 is present in the human cells as a family of functionally different isoforms which are transcribed from alternative promoters. Here, we have demonstrated that expression patterns of Oct-1 isoforms change during differentiation of hematopoetic progenitor cells (CD34+) (HPCs) to the B (CD19+) and T (CD3+) cells. While Oct-1L is expressed at a high level in the CD34+ HPCs, its expression level drops dramatically during the T-cell differentiation, although remains nearly the same in B-cells. We have described the novel human Oct-1R isoform which is conserved in mammals and is B cell-specific. Oct-1R was found in B cells, but not in HPCs. Oct-1R is transcribed from the same promoter as Oct-1L, another lymphocyte-specific isoform. Overexpression of Oct-1R and Oct-1L in the Namalwa cells leads to the repression of many genes involved in B-lymphocyte differentiation and signal transduction. Thus these isoforms may regulate the particular stages of development of normal B cells and maintain their proper differentiation status. However the extremely high level of Oct-1L isoform observed in the B-lymphoblast tumor cell lines indicated that the excess of Oct-L seem likely to considerably decrease the differentiation ability of these cells. Oct-1 may serve as a therapeutic target for many tumors, but it should be noted that in a tumor the content of a certain isoform Oct-1, rather than the total Oct-1 protein, can be increased.

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