The regulatory interplay between Oct-1 isoforms contributes to hematopoiesis and the isoforms imbalance correlates with a malignant transformation of B cells

Abstract

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.

A herpesvirus transactivator and cellular POU proteins extensively regulate DNA binding of the host Notch signaling protein RBP-Jκ to the virus genome

“…S5). A well-established mechanism for transcriptional control in the POU family occurs when different family members or alternatively-spliced forms compete for the same binding site (53,60); in this regard, although we did not detect over-representation of the POU2F2 (Oct-2) motif near the RBP-J peaks, Oct-2 has previously been shown to inhibit auto-activation of Rta by preventing binding of Oct-1 and Rta to the Rta promoter (61). However, we think it is unlikely that Oct-1 regulates the reactivation switch independently because its expression is undetectable during latency and is only induced during reactivation, and ectopic Oct-1 siRNAs did not reactivate latent virus (Fig.…”

Oct1/Pou2f1 is selectively required for colon regeneration and regulates colon malignancy

“…Of note, similar opposing roles were recently described for the Drosophila Oct1 ortholog, Nubbin, based on its different isoforms [60]. Different mammalian Oct1 isoforms have been described [61, 62], and thus Oct1 may regulate normal and malignant epithelial tissue states through evolutionarily conserved mechanisms.…”

GSK3 Kinase Inhibitor, CHIR, Suppress Transcription of Tissue Specific POU2F1 Isoform in Burkitt Namalwa Lymphoma Cells

“…The ability of Oct-1 to regulate a wide range of functionally different genes and processes is based on its ability to interact with various DNA sites [5] and undergo multiple posttranslational modifications. Oct-1 isoforms differing in the sequence of the N-terminal domain are transcribed from alternative promoters and regulate a large number of target genes, both individual for each isoform and common for all Oct-1 isoforms [4,[6][7][8].…”

“…Oct-1 isoforms are expressed in normal cells at certain ratios that are relatively stable for certain cell types [ 4 , 7 , 8 ]. Disturbance in the expression level of some Oct-1 isoforms is observed in many types of tumor tissues and is associated with dysregulation of alternative promoters of the POU2F1 ( Oct-1 ) gene in tumor cells.…”

“…Disturbance in the expression level of some Oct-1 isoforms is observed in many types of tumor tissues and is associated with dysregulation of alternative promoters of the POU2F1 ( Oct-1 ) gene in tumor cells. For example, in Burkitt Namalwa B-cell lymphoma, the concentration of the tissue-specific isoform Oct-1L is several times higher than in normal B cells [ 4 , 8 ].…”