Liu, Yu-Zhen; (1997) Regulation of gene expression by POU family transcription factors. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

A repressor domain in the N-terminus of Oct-2 (amino acids 142-181) is responsible for the inhibitory effects by the POU family transcription factor Oct-2 in neuronal cells. This report describes that the repressor domain can inhibit activation by different classes of activation domains and repress transcription in a distance-independent manner. This effect is observed however, only on TATA box-containing promoters and not on promoters containing an initiator motif, indicating that the inhibitory domain is likely to act by contacting a common downstream target of activation domains within the basal transcriptional complex formed at the TATA box. A mutant containing substitutions of a lysine residue and an arginine for the glutamine at position 167 and the proline at position 175 can abolish repression activity of the repressor domain. Functional interaction occurs between the HIV-1 Tat protein and the Oct-2 repressor domain as well as the corresponding region of Oct-1 to the Oct-2 repressor domain, resulting in the combination of the two factors activating transcription. There are several octamer-like motifs in the HIV-1 LTR. Oct-1 and Oct-2 can inhibit both basal HIV-1 LTR activity and Tat-mediated transactivation. The C-terminus of Oct-1 is mapped to be required for the strong inhibitory effect on the HIV-1 promoter. The herpes simplex virus immediate-early (IE) promoters contain the TAATGARAT motif which acts as a target site for the POU proteins Oct-1, Oct-2 and Brn-3. This study shows that Brn-3a can activate the IE promoters whereas Brn-3b represses IE promoter activity. Furthermore, Brn-3 proteins cannot overcome the inhibitory effect of neuronal Oct-2 on IE promoters nor do they prevent transactivation of the IE promoters by the Oct-1/VP16 complex. Both the primary transcripts of Brn-3a and Brn-3b genes are alternatively spliced to produce two distinct mRNAs encoding long and short isoforms which have differential function. This report describes that the alternative splicing process is regulated in different neuronal-containing tissues and in cultured primary and immortalized neuronal cells.

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