Hunt K K, Fleming J B, Abramian A, Zhang L, Evans D B, Chiao P J
Department of Surgical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston 77030, USA.
Cancer Res. 1998 Dec 15;58(24):5656-61.
The Smad4/DPC4 protein functions as a key transcription factor in transforming growth factor beta (TGF-beta) signaling pathways. However, the downstream target genes regulated by Smad4/DPC4 have not been identified until now. We previously demonstrated that the loss of TGF-beta-induced p21waf1 expression and growth inhibition correlates with inactivation of the Smad4/DPC4 gene. Now we show that transient overexpression of Smad4/DPC4 can induce p21waf1 expression, specific Smad4 DNA binding activity, SBE4-luc reporter gene activity, and subsequent growth inhibition in Smad4/DPC4-null cells and other carcinoma cells in the presence or absence of TGF-beta. Taken together, these data show that p21waf1 is one of the Smad4/DPC4-regulated downstream target genes and suggest that overexpression of the Smad4/DPC4 gene can bypass TGF-beta receptor activation and reestablish one of the key regulatory controls of cell proliferation.
Smad4/DPC4蛋白在转化生长因子β（TGF-β）信号通路中作为关键转录因子发挥作用。然而，迄今为止，由Smad4/DPC4调控的下游靶基因尚未得到鉴定。我们之前证明，TGF-β诱导的p21waf1表达缺失和生长抑制与Smad4/DPC4基因的失活相关。现在我们表明，在存在或不存在TGF-β的情况下，Smad4/DPC4的瞬时过表达均可诱导p21waf1表达、特异性Smad4 DNA结合活性、SBE4-荧光素酶报告基因活性，以及随后在Smad4/DPC4基因缺失的细胞和其他癌细胞中的生长抑制。综上所述，这些数据表明p21waf1是Smad4/DPC4调控的下游靶基因之一，并提示Smad4/DPC4基因的过表达可绕过TGF-β受体激活并重建细胞增殖的关键调控机制之一。
