A molecular scaffold HIC-5-and KLF4-dependent mechanism transactivates p21^<Cip1> in response to loss of anchorage

在这项研究中，我们发现HIC-5还参与了非贴壁细胞中细胞周期蛋白依赖性激酶抑制因子(CKI)p21^和Cip1的转录上调，从而导致生长停滞。P21^&lt；Cip1&gt；的反式激活是在上游元件指定的脱离反应元件(DRE)上调节的，DRE由两个转录因子KRUPEL样KLF4和矮小相关的RUNX1的结合位点组成；这两个位点是反式激活所必需的，但不是单独的充分条件。HIC-5通过促进KLF4在DNA位点上的拴系过程以及在非附着条件下增加其对核基质的定位而关键地参与了反式激活。在RUNX1位点，一个仅有LIM的蛋白CRP2在贴壁条件下实施负调控，假设在失去锚定后被移除，并与KLF4位点的调控一起促进DRE转录活性的提高。总而言之，这项研究揭示了一种新的转录机制，以一种脱离依赖的方式调节基因表达。

In this study, we show that HIC-5 is also engaged in transcriptional upregulation of a cyclin-dependent kinase inhibitor(CKI) p21^<Cip1> in non-adherent cells, thereby contributing to the growth arrest. The transactivation of p21^<Cip1> was regulated at the upstream element, designate detachment-responsive element(DRE), consisting of binding sites for the two transcription factors, Kruppel-like KLF4 and runt-related RUNX1 ; Both sites were necessary but not sufficient alone for the transactivation. HIC-5 was critically involved in the transactivation by facilitating the tethering process of KLF4 onto the DNA sites in association with its increased localization to the nuclear matrix under non-adherent conditions. At the Runx1 site, a LIM-only protein, CRP2, imposed negative regulation under adherent conditions, which was assumingly removed upon loss of anchorage and contributed to the elevated transcriptional activity of DRE collaboratively with the regulation at the KLF4 sites. In conclusion, this study uncovered a novel transcriptional mechanism regulating gene expression in a detachment-dependent manner.