TORC: a new twist on corticotropin-releasing hormone gene expression.

CRH is the principal hypothalamic neurohormone responsible for hypothalamic-pituitary adrenal (HPA) axis activity (1). CRH also serves as an important transsynaptic signal in various neurocircuits in the brain that regulate behavioral and emotional responses to stress (2). Thus, CRH appears to be a key molecule in the coordination of behavioral and neuroendocrine responses to stressful events. Dysregulation of CRH neuronal function is associated with stress-related psychiatric disorders, and abnormal CRH neuropeptide production levels appear to underlie some of this neuronal dysregulation (3). Consequently, there is much interest in determining the regulation of CRH gene expression, with a particular eye on identifying new regulatory proteins that may point to candidate genes for disease susceptibility (4). Studies find that there is high basal CRH gene expression within the medial parvocellular portion of the hypothalamic paraventricular nucleus. However, CRH gene expression is also rapidly increased by various excitatory stimuli that lead to HPA axis activation (5, 6). The coupling of neuronal excitation with CRH gene induction appears to be largely driven by protein kinase A (PKA)-mediated activation of the transcription factor cAMP response element binding protein (CREB) (7, 8). But some recent findings have thrown a wrench in this straightforward understanding of CRH gene expression. Liu et al. (9) noted that, in a hypothalamic-derived neuronal cell line (4B cells) and hypothalamic primary neuronal cultures, treatment with either the phorbol ester phorbol-12-myristate-13-acetate (PMA; protein kinase C activator) or forskolin (adenylate cyclase activator) led to CREB activation (phosphorylation of CREB ser133). Paradoxically, however, only forskolin treatment was sufficient to stimulate CRH gene promoter activity and CRH gene expression, even though this stimulatory activity required CREB activation (9). A related phenomenon has been observed in vivo: microinfusion of forskolin but not phorbol ester in the rat paraventricular nucleus led to increased CRH gene expression, even though both drugs led to increased HPA axis hormone secretion (10). These findings prompted Liu et al. (9) to consider the possible role of a CREB coregulatory factor in the regulation of CRH gene expression. Such a factor would have to meet three conditions. It would have to be rapidly activated by stimulatory intercellular signals, activated by forskolin but not PMA, and dependent on CREB for CRH gene transactivation capability. In the current issue of Endocrinology, Liu et al. (11) explored the possibility that the recently discovered transducer of regulated CREB activity (TORC), which is also known as CREB-regulated transcription coactivator, could be such a factor. Two groups independently discovered this evolutionarily conserved family of CREB coactivators (TORC1, TORC2, and TORC3) by use of high-throughput screening strategies for proteins that potentiated CREB-dependent gene expression (12, 13). Subsequent studies in various peripheral tissue cell lines have found that TORC has a number of interesting biochemical features. These features not only account for TORC’s ability to interact with CREB protein and thereby permit CREB-dependent gene expression, but they also provide for diverse ways in which TORC can be activated or deactivated. TORC binds to the dimerization and DNA binding domain of CREB. Although this interaction does not appear to alter CREB’s DNA binding capability, it enhances CREB’s association with TAFII130, a component of the general transcription