HAUSP, a novel deubiquitinase for Rb - MDM2 the critical regulator.
Tumor suppressor retinoblastoma-associated protein (Rb) is an important cell cycle regulator, arresting cells in early G1. It is commonly inactivated in cancers and its level is maintained during the cell cycle. Rb is regulated by various post-translational modifications such as phosphorylation, acetylation, ubiquitination and so on. Several E3 ligases including murine double minute 2 (MDM2) promote the degradation of Rb. This study focuses on the role of HAUSP (herpes virus associated ubiquitin specific protease) on Rb. Here, we show that HAUSP colocalizes and interacts with Rb to stabilize it from proteasomal degradation by removing wild-type and K48-linked ubiquitin chains in human embryonic kidney 293 (HEK293) cells. HAUSP deubiquitinates Rb in vivo and in vitro, leading to an increased cell population in the G1 phase. Hence, HAUSP is a novel deubiquitinase for Rb. Immunohistochemistry, western blotting and cell-based assays show that HAUSP is overexpressed in glioma and contributes towards glioma progression. However, HAUSP activity on Rb is abrogated in glioma (cancer), where these two proteins show an inverse relationship. MDM2 (a known substrate of HAUSP) serves as a better target for HAUSP-mediated deubiquitination in cancer cells, facilitating degradation of Rb and oncogenic progression. This novel regulatory axis is proteasome mediated, p53 independent, and the level of MDM2 is critical. The shift in equilibrium by differential deubiquitination in regulation of Rb explains a subtle difference existing between normal and cancer cells. This leads to speculation about a new possibility for distinguishing cancer cells from normal cells at the molecular level, which may be investigated for therapeutic intervention in the future.
Signal Transduction in Cancer and Stem Cells Laboratory, Division of Cancer Biology and Inflammatory Disorder, Council of Scientific and Industrial Research - Indian Institute of Chemical Biology, Jadavpur, Kolkata, -700 032, India.
Seemana
S
Bhattacharya
Mrinal K
MK
Ghosh
D000595:Amino Acid Sequence; D000818:Animals; D019556:COS Cells; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D005910:Glioma / Q000201:enzymology; D057809:HEK293 Cells; D006801:Humans; D008969:Molecular Sequence Data; D021381:Protein Transport; D059748:Proteolysis; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism*; D016160:Retinoblastoma Protein / Q000378:metabolism*; D043222:Ubiquitin Thiolesterase / Q000502:physiology*; D000076084:Ubiquitin-Specific Peptidase 7; D054875:Ubiquitination
D016160:Retinoblastoma Protein; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; C464569:USP7 protein, human; D043222:Ubiquitin Thiolesterase; D000076084:Ubiquitin-Specific Peptidase 7
Rb; deubiquitination; glioma; herpes virus associated ubiquitin specific protease; murine double minute 2