RHAMM is differentially expressed in the cell cycle and downregulated by the tumor suppressor p53

Abstract

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 wild-type 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.