
Am J Cancer Res 2012;2(5):492-507
Original Article
High levels of Hdmx promote cell growth in a subset of uveal melanomas
Job de Lange, Amina FAS Teunisse, Matty Verlaan-de Vries, Kirsten Lodder, Suzanne Lam, Gregorius PM Luyten, Federico
Bernal, Martine J Jager, Aart G Jochemsen
Department of Molecular Cell Biology, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands;
Department of Ophthalmology, Leiden University Medical Center,PO Box 9600, 2300 RC Leiden, The Netherlands; Metabolism
Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-1374, USA
Received June 25, 2012; accepted July 21, 2012; Epub August 20, 2012; Published September 15, 2012
Abstract: The p53 tumor suppressor pathway is inactivated in cancer either via direct mutation or via deregulation of upstream
regulators or downstream effectors. P53 mutations are rare in uveal melanoma. Here we investigated the role of the p53
inhibitor Hdmx in uveal melanoma. We found Hdmx over-expression in a subset of uveal melanoma cell lines and fresh-frozen
tumor samples. Hdmx depletion resulted in cell-line dependent growth inhibition, apparently correlating with differential Hdm2
levels. Surprisingly, p53 knockdown hardly rescued cell cycle arrest and apoptosis induction upon Hdmx knockdown, whereas it
effectively prevented growth suppression induced by the potent p53 activator Nutlin-3. In addition, two compounds inhibiting
Hdmx function or expression, SAH-p53-8 and XI-011, also elicited a growth inhibitory effect in a partly p53-independent manner.
These findings suggest a novel, growth-promoting function of Hdmx that does not rely on its ability to inhibit p53. We provide
evidence for a contribution of p27 protein induction to the observed p53-independent G1 arrest in response to Hdmx knockdown.
In conclusion, our study establishes the importance of Hdmx as an oncogene in a subset of uveal melanomas and widens the
spectrum of its function beyond p53 inhibition. (AJCR0000133).
Keywords: Uveal melanoma, Hdmx, p53, Nutlin-3, p27, SAH-p53-8, XI-011, retinoblastoma
Address all correspondence to:
Dr. Aart G Jochemsen
Department of Molecular Cell Biology
Leiden University Medical Center
PO Box 9600, 2300 RC Leiden
The Netherlands.
E-mail: A.G.Jochemsen@lumc.nl
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