Activity-dependent hepatocyte growth factor expression and its role in organogenesis and cancer growth suppression

Abstract

Studies by Murphy et al. have shown that neuronal stimulation can activate immediate early genes that code for transcription factors. Recent data suggest that Ca 2+ elevation in both neuronal cytoplasmic and nuclear compartments is responsible for the coupling of synaptic excitation to gene expression. Deisseroth et al. suggest that Ca 2+ influx through L-type voltage-sensitive Ca 2+ channels (VSCCs) activates cytoplasmic Ca 2+ targets such as calmodulin (CaM). The Ca 2+–CaM complex then translocates to the nucleus leading to Ca 2+ and cAMP response element-binding protein (CREB) phosphorylation and gene expression. Reports have shown that L-type VSCCs are found on the vagus nerve. Other studies have suggested that activation of L-type VSCCs leads to a Ca 2+ store-dependent elevation of nuclear [Ca 2+] that triggers gene expression by more direct activation of nuclear Ca 2+/CaM-dependent protein kinase (CaMK). Moreover, nuclear transcription factors such as DREAM are themselves Ca 2+-dependent, further supporting the importance of both nuclear and cytoplasmic Ca 2+ elevation in regulating gene expression. Our simulation studies suggest that intense synaptic stimulation in combination with amplification by release from intracellular Ca 2+ stores can produce elevations in nuclear Ca 2+ concentration and CaMK phosphorylation leading to CREB phosphorylation and gene expression. One of the downstream events would be the production of hepatocyte growth factor (HGF). HGF has trophic, repair, therapeutic or mitotic effect on kidney, pancreas, spleen, liver, lung, heart and spinal cord. These organs and systems' regeneration can be achieved by either upregulation of HGF release from the vagus nerve or upregulation of HGF production within the system (spinal cord). Conversely, inhibition of HGF release from the vagus nerve can inhibit cancer growth. Vagus nerve seems to be the nerve that nature intends to regulate organ growth and regeneration, it is very possible that other than HGF and injurin, other growth factors could be found in the vagus nerve. Electrical depolarization and hyperpolarization of the vagus nerve would be the most natural and effective way to induce organ regeneration and suppress cancer growth, respectively. A similar pathway seems to exist for different organs as HGF has trophic, repair, therapeutic or mitotic effect on different vagally innervated organs.