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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Functional identification of distinct sets of antitumor activities mediated by the FKBP gene family
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Functional identification of distinct sets of antitumor activities mediated by the FKBP gene family

机译：FKBP基因家族介导的不同组抗肿瘤活性的功能鉴定

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摘要

Assigning biologic function to the many sequenced but still un-characterized genes remains the greatest obstacle confronting the human genome project. Differential gene expression profiling routinely detects uncharacterized genes aberrantly expressed in conditions such as cancer but cannot determine which genes are functionally involved in such complex phenotypes. Integrating gene expression profiling with specific modulation of gene expression in relevant disease models can identify complex biologic functions controlled by currently uncharacterized genes. Here, we used systemic gene transfer in tumor-bearing mice to identify novel antiinvasive and antimetastatic functions for Fkbp8, and subsequently for Fkbp1a. Fkbp8 is a previously uncharacterized member of the FK-506-binding protein (FKBP) gene family down-regulated in aggressive tumors. Antitumor effects produced by Fkbp1a gene expression are mediated by cellular pathways entirely distinct from those responsible for antitumor effects produced by Fkbp1a binding to its bacterially derived ligand, rapamycin. We then used gene expression profiling to identify syndecan 1 (Sdc1) and matrix metalloproteinase 9 (MMP9) as genes directly regulated by Fkbpla and Fkbp8. FKBP gene expression coordinately induces the expression of the antiinvasive Sdc1 gene and suppresses the proinvasive MMP9 gene. Conversely, short interfering RNA-medi-ated suppression of Fkbpla increases tumor cell invasion and MMP9 levels, while down-regulating Sdc1. Thus, syndecan 1 and MMP9 appear to mediate the antiinvasive and antimetastatic effects produced by FKBP gene expression. These studies show that uncharacterized genes differentially expressed in metastatic cancers can play important functional roles in the metastatic phenotype. Furthermore, identifying gene regulatory networks that function to control tumor progression may permit more accurate modeling of the complex molecular mechanisms of this disease.
机译：为许多已测序但仍未表征的基因赋予生物学功能仍然是人类基因组计划面临的最大障碍。差异基因表达谱分析通常检测在癌症等疾病中异常表达的未表征基因，但无法确定哪些基因在功能上参与了此类复杂表型。在相关疾病模型中将基因表达谱与基因表达的特定调节相结合，可以确定由当前未表征的基因控制的复杂生物学功能。在这里，我们使用系统的基因转移在荷瘤小鼠中确定了Fkbp8，然后是Fkbp1a的新型抗侵袭和抗转移功能。 Fkbp8是在侵袭性肿瘤中下调的FK-506结合蛋白（FKBP）基因家族的先前未表征的成员。由Fkbp1a基因表达产生的抗肿瘤作用是通过细胞途径介导的，这些途径完全不同于由Fkbp1a与其细菌衍生的配体雷帕霉素结合产生的抗肿瘤作用。然后，我们使用基因表达谱来鉴定syndecan 1（Sdc1）和基质金属蛋白酶9（MMP9）作为直接由Fkbpla和Fkbp8调控的基因。 FKBP基因表达协调地诱导抗侵袭性Sdc1基因的表达并抑制了侵袭性MMP9基因。相反，短时干扰RNA介导的Fkbpla抑制会增加肿瘤细胞的侵袭和MMP9水平，同时下调Sdc1。因此，Syndecan 1和MMP9似乎介导了FKBP基因表达产生的抗侵袭和抗转移作用。这些研究表明，在转移性癌症中差异表达的未表征基因可以在转移表型中发挥重要的功能作用。此外，鉴定具有控制肿瘤进展功能的基因调控网络可允许对该疾病的复杂分子机制进行更准确的建模。

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