FOXM1 is a downstream target of Gli1 in basal cell carcinomas.
FOXM1 is a downstream target of Gli1 in basal cell carcinomas.
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发表时间：
2002-08
期刊：
影响因子：
11.2
通讯作者：
M. Teh;Soon-Tee Wong;G. Neill;L. Ghali;M. Philpott;A. Quinn
中科院分区：
文献类型：
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作者：
M. Teh;Soon-Tee Wong;G. Neill;L. Ghali;M. Philpott;A. Quinn
叉头盒（FOX）蛋白在调节细胞生长、增殖、分化、寿命和转化相关基因的表达中发挥重要作用。该基因家族在正常人体皮肤生理和疾病过程中的功能重要性尚不清楚。Sonic Hedgehog （Shh）信号的激活在人类皮肤基底细胞癌（bcc）的发展中起着关键作用。最近的研究已经证实，一些FOX基因是Shh信号的下游靶点。我们研究了FOX蛋白在人类皮肤Shh转导中的作用，通过退化PCR鉴定了FOX基因在bcc中的差异表达。在人类皮肤和培养的角化细胞中检测到所有三种已知的FOXM1亚型（a， b和c），并且发现转录活性FOXM1b亚型在bcc中上调。实时定量RT-PCR显示FOXM1 mRNA水平的升高是bcc特异性的，而不是细胞增殖增加的反映，因为在鳞状细胞癌或增殖的原代人角质细胞培养物中没有观察到上调。免疫染色研究显示，整个BCC肿瘤岛都有强烈的核和细胞质染色，而不局限于肿瘤的外围区域，那里增殖的ki -67免疫阳性细胞主要局限于局部。Shh靶胶质瘤转录因子-1 （Gli1）在原代角质形成细胞和其他细胞系中的表达导致FOXM1 mRNA水平和转录活性显著升高，表明FOXM1是Gli1的下游靶点。我们的数据提供了第一个证据，证明通过Gli1激活Shh信号是哺乳动物细胞中FOXM1表达的重要决定因素。考虑到FOXM1在细胞增殖中的作用，FOXM1在bcc中的上调可能是Shh信号对基底角化细胞发挥有丝分裂作用的机制之一，从而导致这种常见的人类癌症的发展。
Forkhead box (FOX) proteins have been shown to play important roles in regulating the expression of genes involved in cell growth, proliferation, differentiation, longevity, and transformation. The functional importance of this gene family in normal human skin physiology and disease processes is not well understood. Activation of Sonic Hedgehog (Shh) signaling plays a key role in the development of basal cell carcinomas (BCCs) of the skin in humans. Recent studies have established that some FOX genes are downstream targets of Shh signaling. We have investigated the role of FOX proteins in transducing Shh effects in human skin by using degenerate PCR to identify FOX genes differentially expressed in BCCs. All three known FOXM1 isoforms (a, b, and c) were detected in human skin and cultured keratinocytes, and the transcriptionally active FOXM1b isoform was found to be up-regulated in BCCs. Real-time quantitative RT-PCR showed that the increase in FOXM1 mRNA levels was specific for BCCs and not a reflection of increased cell proliferation in that no up-regulation was seen in squamous cell carcinomas or proliferating primary human keratinocyte cultures. Immunostaining studies showed intense nuclear and cytoplasmic staining throughout BCC tumor islands and not confined to the periphery regions of the tumor where proliferating Ki-67-immunopositive cells are predominantly localized. Expression of the Shh target glioma transcription factor-1 (Gli1) in primary keratinocytes and other cell lines caused a significant elevation of FOXM1 mRNA level and transcriptional activity, indicating that FOXM1 is a downstream target of Gli1. Our data provide the first evidence that activation of Shh signaling via Gli1 is an important determinant of FOXM1 expression in mammalian cells. Given the role of FOXM1 in cell proliferation, the up-regulation of FOXM1 in BCCs may be one of the mechanisms whereby Shh signaling exerts its mitogenic effect on basal keratinocytes, leading to the development of this common human cancer.