Brn-3a/POU4F1 interacts with and differentially affects p73-mediated transcription

Abstract

The Brn-3a/POU4F1 POU transcription factor is critical for the survival and differentiation of specific sensory neurons during development or upon injury; by regulating expression of target genes, either directly or indirectly upon interaction with other proteins. In this study, we demonstrated the physical interaction of Brn-3a with different p73 isoforms and showed co-localization in sensory neurons arising from the neural crest. The biological effects of p73/ Brn-3a interaction depend on the particular p73 isoform, because co-expression of Brn-3a with TAp73 enhanced cell cycle arrest, whereas Brn-3a and DNp73 cooperated to increase protection from apoptosis. Brn-3a antagonized TAp73 transactivation of pro-apoptotic Bax, but cooperated to increase transcription of the cell cycle regulator p21 CIP1/Waf1 . The region 425-494 amino acids within the TAp73 C terminus were critical for Brn-3a to repress Bax transactivation, but not for cooperation on the p21 CIP1/Waf1 promoter. Our results suggest that co-factors binding to the p73 C terminus facilitate maximal activation on the Bax but not p21 CIP1/Waf1 promoter and that Brn-3a modulates this interaction. Thus, the physical interaction of Brn-3a with specific p73 isoforms will be critical for determining cell fate during neuronal development or in injured neurons expressing both factors. Cell Death and Differentiation (2008) The Brn-3a POU transcription factor (also referred to as POU4F1) is expressed in sensory neurons of the central nervous system and peripheral nervous system, for review see Phillips K and Luisi B; Latchman DS. 1,2 It is essential for the survival and normal differentiation of these neurons during development since loss of Brn-3a in knockout (KO) mice results in extensive apoptosis of somato-sensory neurons with subsequent death of mutants mice by postnatal day 1 (P1). 3,4 Brn-3a enhances the survival of neuronal cultures prepared from dorsal root ganglia and trigeminal ganglia following neurotrophic withdrawal, whereas loss of Brn-3a results in apoptosis even in the presence of neurotrophic factors. 5,6 Increasing Brn-3a also enhances neuronal survival following nerve injury, for example in sciatic nerve crush. 7 Brn3a is also important for neuronal differentiation since Brn-3a KO mice have defects in neurite outgrowth. 8 Brn-3a/bax double KO mutants were used to further dissect these events since sensory neurons in these double KO survived during development but failed to express the Brn-3a target gene, TrkA, and showed abnormal differentiation. 9 Brn-3a exists as two isoforms that are identical in the C terminus containing the POU domain, but the longer 46 kDa Brn-3a(l) contains an amino N-terminal transactivation domain (TAD) that is absent in the shorter 35 kDa Brn-3a(s) protein, 10 (see Figure 2a). Brn-3a(l) is essential for neuronal survival because mutant mice lacking the N-terminal TAD alone demonstrate neuronal loss and lethality, similar to full Brn-3a KO mice. 11The p53 family proteins, namely p53, p63 and p73, are structurally rela...

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