Zhu Y S, Brodsky M, Franklin S O, Huang T, Inturrisi C E
Department of Pharmacology, Cornell University Medical College, New York, New York 10021.
Mol Pharmacol. 1993 Aug;44(2):328-35.
The immediate-early gene c-fos (a nuclear transcription factor) has been viewed as a nuclear "third messenger" or cellular "master switch." Both in vitro and in vivo studies have suggested that the proenkephalin (Penk) and tyrosine hydroxylase (TH) genes are potential targets of this immediate-early gene. We investigated the relationships between the activation of the c-fos gene and the activation of the Penk and TH genes in both rat hippocampus and adrenal using a commonly used model, metrazole (MTZ)-induced convulsions. The administration of MTZ produced a sequential elevation in c-fos, preproenkephalin (PPenk), and TH mRNAs. One hour after MTZ administration, c-fos mRNA was increased about 10-fold in rat hippocampus and about 5-fold in rat adrenal, without a significant change in spinal cord levels. Immunocytochemistry revealed that Fos-like immunoreactivity was greatly increased in both hippocampus and adrenal medulla at 3 hr after MTZ administration. The levels of PPenk and TH mRNAs were significantly increased (5-fold and 3-fold, respectively) in the adrenal 6 hr after MTZ treatment. The effects of MTZ on c-fos, PPenk, and TH mRNAs were dose dependent in both adrenal and hippocampus. In the adrenal, both the basal levels and the MTZ induction of PPenk mRNA were significantly attenuated by hypophysectomy (hypox) and were partially reinstated by adrenocorticotropic hormone (ACTH) replacement. In contrast, the basal levels of c-fos and TH mRNAs were not altered in hypox rat adrenal. ACTH treatment completely blocked the MTZ induction of adrenal c-fos mRNA and the subsequent induction of Fos-like immunoreactivity, whereas MTZ increased PPenk and TH mRNAs nearly 3-fold. Thus, in hypox rats MTZ can increase adrenal c-fos and TH mRNA levels without a corresponding increase in PPenk mRNA, whereas in ACTH-treated rats PPenk and TH mRNA levels in adrenal can be increased by MTZ without a preceding increase in c-fos mRNA. The MTZ induction of c-fos appears neither sufficient nor always necessary for the subsequent MTZ induction of Penk and TH gene expression. We conclude that c-fos, Penk, and TH genes can be differentially regulated in the adrenal of hypox rats or animals treated with ACTH, although they are co-localized in the same medullary cells.
即刻早期基因c-fos（一种核转录因子）被视为核“第三信使”或细胞“主开关”。体外和体内研究均表明，前脑啡肽（Penk）基因和酪氨酸羟化酶（TH）基因是这种即刻早期基因的潜在靶点。我们使用常用模型戊四氮（MTZ）诱导惊厥，研究了大鼠海马体和肾上腺中c-fos基因激活与Penk和TH基因激活之间的关系。给予MTZ后，c-fos、前脑啡肽原（PPenk）和TH mRNA呈序贯性升高。给予MTZ 1小时后，大鼠海马体中c-fos mRNA增加约10倍，大鼠肾上腺中增加约5倍，脊髓水平无显著变化。免疫细胞化学显示，给予MTZ 3小时后，海马体和肾上腺髓质中Fos样免疫反应性均显著增加。MTZ处理6小时后，肾上腺中PPenk和TH mRNA水平显著升高（分别为5倍和3倍）。MTZ对肾上腺和海马体中c-fos、PPenk和TH mRNA的影响呈剂量依赖性。在肾上腺中，垂体切除（hypox）显著减弱了PPenk mRNA的基础水平和MTZ诱导作用，促肾上腺皮质激素（ACTH）替代可部分恢复。相反，hypox大鼠肾上腺中c-fos和TH mRNA的基础水平未改变。ACTH处理完全阻断了MTZ诱导的肾上腺c-fos mRNA以及随后的Fos样免疫反应性诱导，而MTZ使PPenk和TH mRNA增加近3倍。因此，在hypox大鼠中，MTZ可增加肾上腺c-fos和TH mRNA水平，而PPenk mRNA无相应增加，而在ACTH处理的大鼠中，MTZ可增加肾上腺中PPenk和TH mRNA水平，而c-fos mRNA无预先增加。MTZ诱导c-fos对于随后MTZ诱导Penk和TH基因表达似乎既不充分也非总是必要。我们得出结论，尽管c-fos、Penk和TH基因共定位于同一髓质细胞中，但在hypox大鼠或接受ACTH处理的动物的肾上腺中，它们可受到不同调节。
