RHAMM is differentially expressed in the cell cycle and downregulated by the tumor suppressor p53
RHAMM is differentially expressed in the cell cycle and downregulated by the tumor suppressor p53
复制标题
DOI：
10.4161/cc.7.21.7014
复制
发表时间：
2008-11-01
期刊：
影响因子：
4.3
通讯作者：
Engeland, Kurt
中科院分区：
文献类型：
--
作者：
Sohr, Sindy;Engeland, Kurt
透明质酸介导的运动受体RHAMM在细胞中以及在细胞膜上发挥不同的功能。RHAMM可以输出到细胞表面，在那里它结合透明质酸（HA）并与HA受体CD 44相互作用。细胞运动、伤口愈合和侵袭等过程都受到RHAMM的调节。在细胞内，RHAMM与细胞骨架、微管、中心体和有丝分裂纺锤体相关。它参与控制有丝分裂纺锤体的稳定性和完整性。此外，RHAMM在几种癌组织中过表达。我们发现，RHAMM的表达在细胞周期中受到不同的调节，并且RHAMM的细胞周期依赖性合成在转录水平上由其启动子控制。在细胞周期的早期阶段，RHAMM蛋白水平跟随mRNA表达。而在G（2）/M期，RHAMM mRNA的表达在S期已达高峰，并在达到高峰前下降。此外，RHAMM表达被肿瘤抑制因子p53下调。在转基因p53诱导型细胞系统以及用nutlin-3、多柔比星或紫杉醇处理的野生型p53的细胞中观察到这种调节。报道基因分析表明，p53的阻遏作用在转录水平上受到RHAMM启动子的调控，RHAMM启动子也包含该基因的第一个外显子和第一个内含子。总的来说，我们的数据支持RHAMM已经在S期的作用。此外，p53依赖性下调与RHAMM的致癌功能和最近报道的p53抑制CD 44转录的肿瘤抑制功能一致。
The receptor for hyaluronan-mediated motility RHAMM exerts different functions in the cell as well as on the cell membrane. RHAMM can be exported to the cell surface where it binds hyaluronic acid ( HA) and interacts with the HA receptor CD44. Processes like cell motility, wound healing and invasion are modulated by RHAMM. Intracellularly, RHAMM is associated with the cytoskeleton, microtubules, centrosomes and the mitotic spindle. It participates in the control of mitotic spindle stability and integrity. Furthermore, RHAMM is overexpressed in several cancer tissues. We found that RHAMM expression is differentially regulated during the cell cycle and that cell cycle-dependent synthesis of RHAMM is controlled by its promoter on the transcriptional level. RHAMM protein levels follow mRNA expression in the early phases of the cell cycle. However, they already peak in S phase and decrease before the maximum of RHAMM mRNA expression is reached in G(2)/M. Furthermore, RHAMM expression is downregulated by the tumor suppressor p53. This regulation is observed in a transgenic p53-inducible cell system as well as in cells with wildtype p53 treated with nutlin-3, doxorubicin or paclitaxel. Reporter assays demonstrated that the repression by p53 is regulated on the transcriptional level by the RHAMM promoter also comprising the first exon and the first intron of the gene. In general, our data support a role of RHAMM already in S phase. Additionally, p53-dependent downregulation is consistent with an oncogenic function of RHAMM and the recently reported tumor-suppressive function of CD44 transcriptional repression by p53.