RING-dependent tumor suppression and G2/M arrest induced by the TRC8 hereditary kidney cancer gene.
TRC8/RNF139 and von Hippel-Lindau (VHL) both encode E3 ubiquitin (Ub) ligases mutated in clear-cell renal carcinomas (ccRCC). VHL, inactivated in nearly 70% of ccRCCs, is a tumor suppressor encoding the targeting subunit for a Ub ligase complex that downregulates hypoxia-inducible factor-alpha. TRC8/RNF139 is a putative tumor suppressor containing a sterol-sensing domain and a RING-H2 motif essential for Ub ligase activity. Here we report that human kidney cells are growth inhibited by TRC8. Inhibition is manifested by G2/M arrest, decreased DNA synthesis and increased apoptosis and is dependent upon the Ub ligase activity of the RING domain. Tumor formation in a nude mouse model is inhibited by TRC8 in a RING-dependent manner. Expression of TRC8 represses genes involved in cholesterol and fatty acid biosynthesis that are transcriptionally regulated by the sterol response element binding proteins (SREBPs). Expression of activated SREBP-1a partially restores the growth of TRC8-inhibited cells. These data suggest that TRC8 modulation of SREBP activity comprises a novel regulatory link between growth control and the cholesterol/lipid homeostasis pathway.
Brauweiler
A
A
Division of Medical Oncology, Department of Medicine, University of Colorado at Denver and Health Sciences Center, Aurora, CO 80045-0511, USA.
Lorick
K L
KL
Lee
J P
JP
Tsai
Y C
YC
Chan
D
D
Weissman
A M
AM
Drabkin
H A
HA
Gemmill
R M
RM
D000595:Amino Acid Sequence; D002292:Carcinoma, Renal Cell / Q000235:genetics / Q000473:pathology; D002453:Cell Cycle; D002455:Cell Division; D002784:Cholesterol / Q000096:biosynthesis; D003001:Cloning, Molecular; D016195:G2 Phase; D006801:Humans; D007668:Kidney / Q000166:cytology / Q000502:physiology*; D007680:Kidney Neoplasms / Q000235:genetics* / Q000473:pathology*; D008969:Molecular Sequence Data; D011956:Receptors, Cell Surface / Q000737:chemistry / Q000235:genetics* / Q000502:physiology*
C114025:RNF139 protein, human; D011956:Receptors, Cell Surface; D002784:Cholesterol