Masson, Norma; (1993) Phosphorylation and dimerisation of transcription factor ATF-1. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The CREB/ATF family of 'bZIP' transcription factors bind to promoter elements containing the sequence motif CGTCA and mediate a variety of transcriptional responses. One of the best characterised members is the cAMP-response-element-binding protein, CREB, which plays a critical role in cAMP-inducible transcription. In differentiated cells, PKA directly activates CREB by phosphorylation and CREB in turn can activate several functionally diverse downstream genes. Two other bZIP proteins, ATF-1 and CREM, are highly homologous to CREB, and can heterodimerise with CREB. The role of these CREB homologues, and in particular the role of ATF-1, is poorly understood. Undifferentiated F9 (UF9) cells are refractory to cAMP, but become cAMP-responsive following retinoic acid-induced differentiation. The UF9 cell phenotype is due in part to the presence of a titratable inhibitor of CREB which is lost or inactivated following differentiation. Interestingly, the level of ATF-1 protein (i.e. ATF-1 homodimer and CREB/ATF-1 heterodimer) is dramatically reduced following differentiation. Thus it is possible that ATF-1 may correspond to this inhibitor of CREB, and regulate the cAMP-response during differentiation of F9 cells. In addition, ATF-1 is of particular interest because its conformation is affected by phosphorylation in a cell type-specific manner. By mutational analysis, three serine residues have been identified which in cooperation with the NH2-terminal region are involved in ATF 1 phosphorylation. Interestingly, these serines map to a region that is homologous to a transcriptional activation domain in CREB, suggesting that phosphorylation of ATF-1 may regulate its transcriptional activity. Moreover it appears that ATF-1 phosphorylation is affected by dimerisation and by DNA-binding. This suggests that ATF-1 transcriptional activity may be regulated by phosphorylation in vivo in a highly complex manner.

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