The emerging role of E2F-1 in the DNA damage response and checkpoint control.

Genotoxic stress triggers a myriad of cellular responses including cell cycle arrest, stimulation of {DNA} repair and apoptosis. A central role for the E2F-1 transcription factor in the {DNA} damage response pathway is gaining support. E2F-1 is phosphorylated by {DNA} damage responsive protein kinases, which leads to E2F-1 accumulation and the induction of apoptosis. In addition, emerging information suggests that E2F-1 may play a role in the detection and subsequent repair of damaged DNA

A New Role for E2F-1 in Checkpoint Control

In response to DNA damage, E2F-1 is induced and phosphorylated. Phosphorylated E2F-1 can reside in discrete nuclear structures and induce apoptosis, suggesting a unique role for E2F-1 in DNA repair and checkpoint functions

E2F and cell cycle control: a double-edged sword

The E2F family of transcription factors plays a central role in regulating cellular proliferation by controlling the expression of both the genes required for cell cycle progression, particularly DNA synthesis, and the genes involved with apoptosis. E2F is regulated in a cell cycle-dependent manner, principally through its temporal association with pocket protein family members, the prototype member being the retinoblastoma tumor suppressor protein. Pocket proteins are, in turn, regulated through phosphorylation by cyclin-dependent kinase (cdk). The kinase activity of cyclin/cdk complexes is negatively regulated by cdk inhibitors, and thus both positive and negative growth regulatory signals impinge on E2F activity. Different E2F family members exhibit distinct cell cycle and apoptotic activities. Thus, E2F appears to play a pivotal role in coordinating events connected with proliferation, cell cycle arrest, and apoptosis

HR23B, a biomarker for HDAC inhibitors

As our understanding of cancer biology increases and novel therapies are developed, an increasing number of predictive biomarkers are becoming clinically available. Aberrant acetylation has been strongly linked to tumourigenesis and the modulation of acetylation through targeting histone deacetylase (HDAC) has led to the introduction of many HDAC inhibitors. To date, two have had regulatory approval for the treatment of cutaneous T cell lymphoma (CTCL). Modifications in chromatin control underpin the mechanism of action of HDAC inhibitors. A genome wide loss-of-function screen identified HR23B as a gene that governs sensitivity to HDAC inhibitors. HR23B shuttles ubiquitinated cargo proteins to the proteasome and elevated levels may contribute to cell death mediated by this pathway. It also governs cell sensitivity to drugs that act directly on the proteasome. HDAC inhibitors influence proteasome activity and there may be a synergistic interaction with proteasome inhibitors. HR23B and HDAC6 interact and HDAC6 may be a negative regulator of apoptosis and a positive regulator of autophagy and through its ability to down-regulate HR23B, may impact on the cellular outcome of HDAC inhibitor treatment. Expression of HR23B has been correlated with clinical response to HDAC inhibitors in a retrospective analysis of CTCL patients. The tissue expression of HR23B and the autophagy marker LC3 has been investigated and there may be a reciprocal relationship in their expression in some tumours which may provide prognostic information and patients with low HR23B expression but high levels of autophagy appear to have a particularly poor prognosis. Well designed, biomarker-driven prospective clinical trials are needed to clarify the predictive and prognostic roles of HR23B.This thesis is not currently available in ORA

Mdm2 targets the p53 transcription cofactor JMY for degradation

We define here a new mechanism through which Mdm2 (mouse double minute 2) regulates p53 activity, by targeting the p53 transcription cofactor JMY. DNA damage causes an increase in JMY protein, and, in a similar manner, small molecule inhibitors of Mdm2 activity induce JMY in unperturbed cells. At a mechanistic level, Mdm2 regulation of JMY requires the Mdm2 RING (really interesting new gene) finger, which promotes the ubiquitin-dependent degradation of JMY. However, regulation of JMY occurs independently of the p53-binding domain in Mdm2 and p53 activity. These results define a new functional relationship between the p53 cofactor JMY and Mdm2, and indicate that transcription cofactors that facilitate p53 activity are important targets for Mdm2 in suppressing the p53 response