Fausto N, Mead J E, Braun L, Thompson N L, Panzica M, Goyette M, Bell G I, Shank P R
Department of Pathology, Brown University, Providence, Rhode Island 02912.
Symp Fundam Cancer Res. 1986;39:69-86.
When growth is stimulated in normally quiescent hepatocytes, steady-state levels of c-fos, c-myc, and p53 mRNAs increase sequentially and transiently before DNA replication. C-fos mRNA increases almost immediately after partial hepatectomy and decreases by 2 hr; c-myc mRNA reaches maximal levels between 30 min and 2 hr. In contrast, the p53 mRNA increase corresponds to the G1/S transition, and mRNAs from c-ras genes are elevated later, coinciding with DNA replication and mitosis. p53 and p21 proteins are elevated when their mRNAs are more abundant. This regulated response suggests that these genes either control key steps in the cell cycle or are responding to humoral or internal growth factors acting at specified growth stages. We propose that hepatocytes go through a "priming" stage during the first four hours after partial hepatectomy and that their progression through late G1, is likely to be controlled by autocrine or paracrine mechanisms, which may account for the precisely regulated growth of the liver after partial hepatectomy. Transforming growth factor beta (TGF beta) is a potent inhibitor of DNA synthesis in normal hepatocytes in vitro. We show that TGF beta mRNA increases in the regenerating liver at the time of hepatocyte DNA synthesis and mitosis. In normal or regenerating liver, the mRNA for this growth factor is contained in nonparenchymal cells but not in hepatocytes. We suggest that TGF beta may be a component of a paracrine regulatory loop that controls hepatocyte replication.
当正常静止的肝细胞生长受到刺激时，在DNA复制之前，c-fos、c-myc和p53 mRNA的稳态水平会依次短暂升高。部分肝切除术后，c-fos mRNA几乎立即增加，并在2小时后下降；c-myc mRNA在30分钟至2小时之间达到最高水平。相比之下，p53 mRNA的增加与G1/S期转换相对应，而c-ras基因的mRNA在稍后升高，与DNA复制和有丝分裂同时发生。当p53和p21的mRNA含量增加时，它们的蛋白质水平也会升高。这种调节反应表明，这些基因要么控制细胞周期中的关键步骤，要么对在特定生长阶段起作用的体液或内源性生长因子作出反应。我们提出，肝细胞在部分肝切除术后的最初四个小时内会经历一个“启动”阶段，它们在G1期晚期的进程可能受自分泌或旁分泌机制控制，这可能解释了部分肝切除术后肝脏精确调节的生长过程。转化生长因子β（TGFβ）在体外是正常肝细胞DNA合成的有效抑制剂。我们发现，在肝细胞DNA合成和有丝分裂时，再生肝中TGFβ mRNA增加。在正常或再生肝中，这种生长因子的mRNA存在于非实质细胞中，而不存在于肝细胞中。我们认为，TGFβ可能是控制肝细胞复制的旁分泌调节环的一个组成部分。
