We have previously reported that the AB regions of retinoic acid receptors (RARs and RXRs) contain a transcriptional activation function capable of modulating the activity of the ligand‐dependent activation function present in the C‐terminal DE regions of these receptors. However, we could not demonstrate that these AB regions possess an autonomous activation function similar to the AF‐1s found in the AB regions of steroid hormone receptors. Using the mouse CRBPII promoter as a reporter gene, we now report that the AB regions of RAR alpha, beta and gamma, as well as those of RXR alpha and gamma, contain an autonomous, ligand‐independent activation function, AF‐1, which can efficiently synergize with AF‐2s. Moreover, AF‐1s account for the ligand‐independent, constitutive activation of transcription by RXR alpha and gamma. We also show that RARs and RXRs preferentially heterodimerize in solution in cultured cells in vivo, through the dimerization interface present in their E region, irrespective of the presence of all‐trans or 9‐cis retinoic acid. Furthermore, our results indicate that homodimeric interactions are not observed in cultured cells in vivo under conditions where heterodimeric interactions readily occur, which is in agreement with previous observations showing the preferential binding of RAR‐RXR heterodimers to RA response elements in vitro.
In yeast, sphingoid base synthesis is required for the internalization step of endocytosis and organization of the actin cytoskeleton. We show that overexpression of either one of the two kinases Pkh1p or Pkh2p, that are homologous to mammalian 3-phosphoinositidedependent kinase-1 (PDK1), can speci®cally suppress the sphingoid base synthesis requirement for endocytosis. Pkh1p and Pkh2p have an overlapping function because only a mutant with impaired function of both kinases is defective for endocytosis. Pkh1/2p kinases are activated in vitro by nanomolar concentrations of sphingoid base. These results suggest that Pkh1/2p kinases are part of a sphingoid base-mediated signaling pathway that is required for the internalization step of endocytosis. The Pkc1p kinase that is phosphorylated by Pkh1/2p kinases and plays a role in endocytosis was identi®ed as one of the downstream effectors of this signaling cascade.
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