Role of gut-enriched Kruppel-like factor in colonic cell growth and differentiation
Role of gut-enriched Kruppel-like factor in colonic cell growth and differentiation
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DOI：
10.1152/ajpgi.2000.279.4.g806
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发表时间：
2000-10-01
影响因子：
4.5
通讯作者：
Tseng, CC
中科院分区：
文献类型：
--
作者：
Shie, JL;Chen, ZY;Tseng, CC
癌细胞在许多方面不同于正常细胞，包括过度增殖和分化丧失。最近的研究集中在转录因子在调节异常细胞生长中的作用。肠道富集Kruppel样因子（GKLF）是一种新发现的在胃肠道广泛表达的真核锌指蛋白。在目前的研究中，我们证明了GKLF mRNA水平显着下降，在不典型增生的上皮细胞的结肠，包括腺瘤性息肉和癌症。GKLF免疫染色在正常结肠的表面上皮细胞较高，并逐渐减少向隐窝，但这种梯度不存在于腺瘤和癌粘膜。在人结肠腺癌细胞系HT-29中，GKLF DNA组成性过表达减少[H-3]胸苷掺入，而GKLF基因的抑制增加DNA合成，表明GKLF基因的下调可能有助于细胞过度增殖。过表达GKLF cDNA的HT-29细胞中CD 1蛋白水平和CD 1相关激酶活性降低，CD 1启动子活性被GKLF显著抑制。当HT-29细胞在丁酸钠存在下培养时，GKLF mRNA水平随着细胞获得更多分化表型而增加。这些结果表明，GKLF在调节结肠上皮细胞的生长和分化中起着重要作用，GKLF表达下调可能导致结肠细胞过度增殖。此外，GKLF似乎是CD 1基因的转录阻遏物。
Cancer cells differ from normal cells in many aspects, including hyperproliferation and loss of differentiation. Recent research has focused on the role of transcription factors in regulating abnormal cell growth. Gut-enriched Kruppel-like factor (GKLF) is a newly identified eukaryotic zinc finger protein expressed extensively in the gastrointestinal tract. In the current study, we demonstrated that GKLF mRNA levels were significantly decreased in the dysplastic epithelium of the colon, including adenomatous polyp and cancer. GKLF immunostains in the normal colon were higher at the surface epithelium and gradually decreased toward the crypt, but this gradient was not present in the adenomatous and cancerous mucosa. Constitutive overexpression of GKLF DNA in a human colonic adenocarcinoma cell line (HT-29) decreased [H-3] thymidine incorporation, whereas suppression of GKLF gene increased DNA synthesis, indicating that downregulation of the GKLF gene might contribute to cellular hyperproliferation. Cyclin D1 (CD1) protein level and CD1-associated kinase activity were decreased in HT-29 cell overexpressed GKLF cDNA, and CD1 promoter activity was profoundly suppressed by GKLF. When HT-29 cells were cultured in the presence of sodium butyrate, GKLF mRNA levels increased as cells acquired more differentiated phenotypes. These results suggest that GKLF plays an important role in regulating cell growth and differentiation in the colonic epithelium and that downregulation of GKLF expression may cause colonic cells to become hyperproliferative. Furthermore, GKLF appears to be a transcriptional repressor of the CD1 gene.