多发性骨髓瘤(MM)的发生发展与Ras/Raf/MEK/ERK信号通路持续活化密切相关，申请人前期研究首次证实IQGAP1在MM细胞中过表达并活化Ras/Raf/MEK/ERK通路从而促进多发性骨髓瘤发生发展。但IQGAP1过表达机制尚不明确，IQGAP1基因的转录调控及机制仍然未知。本项目在前期研究基础上提出假说：SP1通过与p300相互作用，调控IQGAP1基因的转录，进而促进多发性骨髓瘤发生发展。本研究拟行1.IQGAP1在MM体内外功能性研究；2.通过生物信息学方法预测并筛选出可能结合在IQGAP1启动子上的转录因子Sp1；3.从细胞株、动物模型、临床标本水平探索SP1/p300复合物在IQGAP1转录中的作用及其转录调控机制。以期寻找调控IQGAP1表达的元件,为MM的生物靶向治疗奠定理论和实验基础。

The occurrence and development of multiple myeloma (MM)is closely related to the continuous activation of Ras/Raf/MEK/ERK signaling pathway. Our previous research had firstly shown that MM cells overexpressed IQGAP1 gene and promoted development of multiple myeloma through activating Ras/Raf/MEK/ERK pathway.But the mechanism of IQGAP1 overexpression and IQGAP1 gene transcription regulation remains uncertain.Based on the previous study,we propose a hypothesis:SP1 interacts with p300 and promotes development of multiple myeloma through regulating IQGAP1 transcription.We devote to complete the following parts:1. The study of the function of IQGAP1 in vitro and vivo.2.Through bioinformatics analysis and prediction we predictited and screened transcription factor Sp1 as a possible upstream regulator of IQGAP1.3.we will explore the role of Sp1 in the transcription of IQGAP1 on the cell lines,animal models and clinical sample’s levels to illustrate that Sp1/p300 Complex regulate the IQGAP1 gene transcription.We aim to find the transcription factor/complex on the promotor sequence of IQGAP1,which will lay the theoretical and experimental bases of multiple myeloma’s biological target therapy.