April 2008

13 April 2008

Arsenic action on leukaemia

Nature Cell Biology doi: 10.1038/ncb1716

Nature Cell Biology doi: 10.1038/ncb1717

Therapeutic use of the poison arsenic to treat acute promyelocytic leukaemia leads to modification of the oncoprotein PML-RARα, causing its degradation. Two studies published online this week in Nature Cell Biology identify an enzyme that modifies proteins for destruction, known as ubiquitin ligase RNF4, as being responsible for recognizing PML-RARα and targeting it for degradation.

Originally identified in 1992 as the active ingredient in a traditional Chinese medicine, arsenic trioxide (ATO) has since been used to treat acute promyelocytic leukemia – a cancer of the blood and bone marrow. However, the mechanism of ATO action had remained unknown. Previous studies have shown that ATO treatment causes modification of PML-RARα by addition of several copies of the signalling molecule SUMO. How this modification correlates with the observed loss of PML-RARα was unclear.

Two studies from Ronald T. Hay and Hugues de The how that RNF4 specifically recognizes the SUMO chains attached to PML-RARα. RNF4 can then add further ubiquitin modifications to target the oncoprotein for degradation by the proteasome. Interestingly, PML-RARα represents the first cellular substrate of RNF4 to be identified.

This work adds vital information into how arsenic and arsenic-related compounds can be used as therapeutic agents to treat haematological cancers and could aid the development of improved treatments.

Author contact:

Ronald T. Hay (University of Dundee, UK)

Tel: +44 1382 386 309; E-mail:r.t.hay@dundee.ac.uk

Hugues de The (CNRS/Universite de Paris, France)

Tel: +33 1 57 27 67 70; E-mail:dethe@univ-paris-diderot.fr

RNF4 is a poly-SUMO-specific E3 ubiquitin ligase required for arsenic-induced PML degradation

Michael H. Tatham, Marie-Claude Geoffroy, Linnan Shen, Anna Plechanovova, Neil Hattersley, Ellis G. Jaffray, Jorma J. Palvimo & Ronald T. Hay

Published online: 13 April 2008; | doi:10.1038/ncb1716

Abstract | Full text

Arsenic degrades PML or PML–RARα through a SUMO-triggered RNF4/ubiquitin-mediated pathway

Valérie Lallemand-Breitenbach, Marion Jeanne, Shirine Benhenda, Rihab Nasr, Ming Lei, Laurent Peres, Jun Zhou, Jun Zhu, Brian Raught & Hugues de Thé

Published online: 13 April 2008; | doi:10.1038/ncb1717

Abstract | Full text

6 April 2008

p53 hampers energy metabolism in cancer cells

Nature Cell Biology doi: 10.1038/ncb1724

The tumour suppressor p53 can limit tumour development by inhibiting aerobic glycolysis reports a paper published online this week in Nature Cell Biology.

Cancer cells normally shift their metabolism to aerobic glycolysis - the conversion of glucose to lactic acid in the presence of oxygen - which confers an advantage in sustaining tumour growth.

p53 activity is lost in over half of human tumours; its primary role is to eliminate cells that have undergone oncogenic transformation by inducing cell growth arrest or programmed cell death. Nobuyuki Tanaka and colleagues found, by looking at p53-deficient primary fibroblasts, that loss of p53 leads to higher glucose metabolism, and demonstrated that this requires de-repression of the transcription factor NF-κB and one of its target genes called GLUT3.

This work reveals an additional function of p53 in restricting cell proliferation through suppression of NF-κB, which is important for maintaining normal levels of glucose metabolism and cell growth.

Author contact:

Nobuyuki Tanaka (Nippon Medical School, Kawasaki-shi, Japan)

Tel: +81 44 733 1860; E-mail:nobuta@nms.ac.jp

p53 regulates glucose metabolism through IKK and NF-κB and inhibits cell transformation

Keiko Kawauchi, Keigo Araki, Kei Tobiume & Nobuyuki Tanaka

Published online: 06 April 2008; | doi:10.1038/ncb1724

Abstract | Full text