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Biomedical subjects

Nicholas B La Thangue

Publications and source records attributed to Nicholas B La Thangue.

At least 19 recordsLinked to original sources
PubMed2026

PRMT5-mediated intron retention triggers innate and adaptive immunity against cancer.

PRMT5 is expressed at high levels in many cancers, where it regulates diverse cellular pathways that contribute to oncogenesis. Here, we have defined a new role for PRMT5 in regulating and coordinating the interplay between the innate and adaptive immune response. This occurs, in part, through the influence of PRMT5 and E2F1 on RNA splicing and the presence of retained introns (RIs). We found that RIs have a propensity to form double-stranded RNAs that contribute to the innate response. Furthermore, many RIs contain non-canonical open-reading frames (ncORFs), which can be translated and then processed into small peptides that assemble with the MHC class I complex. Significantly, RI-derived peptides are highly immunogenic and, as a murine cancer vaccine, carrying a string of antigenic RI peptides, delayed tumour growth and enhanced survival. RIs are present in human tumour cells, and we identified T lymphocytes in human cancer patients, with antigen specificity for RI-derived peptides, that killed human tumour cells in vitro. Regulating intron retention thus offers a new therapeutic approach to enhance tumour immunogenicity.

Animals↗
PubMed2006

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.

Animals↗
PubMed2006

Histone deacetylase inhibitors: gathering pace.

Reversible histone acetylation is one of the key mechanisms involved in the epigenetic control of gene expression. A variety of recent studies has revealed a role for acetylation in a much broader repertoire of physiological processes, including proliferation control and protein folding, and has highlighted how a variety of non-histone regulatory proteins are influenced by acetylation. Inhibition of histone deacetylase (HDAC) prompts tumour cells to enter apoptosis and, as a consequence, several HDAC inhibitors have entered clinical trials. It is likely that HDAC inhibitor drugs will provide an important class of new mechanism-based therapeutics for cancer.

Animals↗
PubMed2006

14-3-3 proteins integrate E2F activity with the DNA damage response.

The E2F family is composed of at least eight E2F and two DP subunits, which in cells exist as E2F/DP heterodimers that bind to and regulate E2F target genes. While DP-1 is an essential and widespread component of E2F, much less is known about the DP-3 subunit, which exists as a number of distinct protein isoforms that differ in several respects including the presence of a nuclear localisation signal (NLS). We show here that the NLS region of DP-3 harbours a binding site for 14-3-3epsilon, and that binding of 14-3-3epsilon alters the cell cycle and apoptotic properties of E2F. DP-3 responds to DNA damage, and the interaction between DP-3 and 14-3-3epsilon is under DNA damage-responsive control. Further, 14-3-3epsilon is present in the promoter region of certain E2F target genes, and reducing 14-3-3epsilon levels induces apoptosis. These results identify a new level of control on E2F activity and, at a more general level, suggest that 14-3-3 proteins integrate E2F activity with the DNA damage response.

14-3-3 Proteins↗
PubMed2006

Chromatin control and cancer-drug discovery: realizing the promise.

Recent years have seen major advances in elucidating the complexity of chromatin and its role as an epigenetic regulator of gene expression in eukaryotes. We now have a basic understanding of chromatin control and the enzymatic modifications that impart diverse regulatory cues to the functional activity of the genome. Most importantly, although research into chromatin has uncovered fascinating insights into the control of gene expression, it has also generated a large body of information that is being harnessed to develop new therapeutic modalities for treating cancer. Here, we discuss recent advances that support the contention that future generations of chromatin-modulating drugs will provide a significant group of new, mechanism-based therapeutics for cancer.

Antineoplastic Agents↗
PubMed2006

DNA-damage-responsive acetylation of pRb regulates binding to E2F-1.

The pRb (retinoblastoma protein) tumour suppressor protein has a crucial role in regulating the G1- to S-phase transition, and its phosphorylation by cyclin-dependent kinases is an established and important mechanism in controlling pRb activity. In addition, the targeted acetylation of lysine (K) residues 873/874 in the carboxy-terminal region of pRb located within a cyclin-dependent kinase-docking site hinders pRb phosphorylation and thereby retains pRb in an active state of growth suppression. Here, we report that the acetylation of pRb K873/874 occurs in response to DNA damage and that acetylation regulates the interaction between the C-terminal E2F-1-specific domain of pRb and E2F-1. These results define a new role for pRb acetylation in the DNA damage signalling pathway, and suggest that the interaction between pRb and E2F-1 is controlled by DNA-damage-dependent acetylation of pRb.

Acetylation↗
PubMed2005

E2F-8: an E2F family member with a similar organization of DNA-binding domains to E2F-7.

E2F is a family of transcription factors implicated in cell cycle control. To understand the role of E2F in controlling cell cycle progression, it is necessary to clarify the breadth of the E2F family. To date, seven E2F subunits have been identified. We report here the characterization of a new E2F subunit, E2F-8, which resembles the organization of E2F-7 in the presence of two separate DNA-binding domains, the integrity of which is required for E2F-8 to bind to DNA. Furthermore, like E2F-7, we find that E2F-8 can repress transcription and delay cell cycle progression. The similarities between E2F-7 and E2F-8 define a new subgroup of the E2F family, and further imply that E2F-7 and E2F-8 may act through overlapping mechanisms in mediating cell cycle control.

Amino Acid Sequence↗
PubMed2005

Signalling DNA damage by regulating p53 co-factor activity.

In response to DNA damage the related phosphatidylinositol-3-OH-kinase-like-kinases ATM and ATR phosphorylate downstream protein targets which facilitate the DNA damage response. A new pathway in which ATM phosphorylates the transcriptional co-factor Strap has been elucidated. Phosphorylation causes the stabilization of nuclear Strap and favours the formation of a stress-responsive co-activator complex. Strap activity enhances p53 acetylation, and augments the response to DNA damage. Most interestingly, in AT cells Strap remains cytoplasmic, and a mutant derivative that cannot be phosphorylated by ATM is similarly localised to the cytoplasm. These results argue that Strap is an important downstream effector in the DNA damage response.

Acetylation↗
PubMed2004

A new effector pathway links ATM kinase with the DNA damage response.

The related kinases ATM (ataxia-telangiectasia mutated) and ATR (ataxia-telangiectasia and Rad3-related) phosphorylate a limited number of downstream protein targets in response to DNA damage. Here we report a new pathway in which ATM kinase signals the DNA damage response by targeting the transcriptional cofactor Strap. ATM phosphorylates Strap at a serine residue, stabilizing nuclear Strap and facilitating formation of a stress-responsive co-activator complex. Strap activity enhances p53 acetylation, and augments the response to DNA damage. Strap remains localized in the cytoplasm in cells derived from ataxia telangiectasia individuals with defective ATM, as well as in cells expressing a Strap mutant that cannot be phosphorylated by ATM. Targeting Strap to the nucleus reinstates protein stabilization and activates the DNA damage response. These results indicate that the nuclear accumulation of Strap is a critical regulator in the damage response, and argue that this function can be assigned to ATM through the DNA damage-dependent phosphorylation of Strap.

Antibodies, Monoclonal↗
PubMed2004

Histone deacetylase inhibitors open new doors in cancer therapy.

Cancer drug development has moved from conventional cytotoxic chemotherapeutics to a more mechanism-based targeted approach towards the common goal of tumour growth arrest. The rapid progress in chromatin research has supplied a plethora of potential targets for intervention in cancer. Here, we focus on the histone deacetylase (HDAC) inhibitors, together with their current status of clinical development and potential utility in cancer therapy. HDACs have been widely implicated in growth and transcriptional control, and inhibition of HDAC activity using small molecules causes apoptosis in tumour cells. We discuss the rationale for the development of HDAC inhibitors as novel anti-cancer agents, the potential clinical application and explore ideas on how we may move towards patient stratification with the possibility of increasing efficacy in the clinic.

Acetylation↗
PubMed2004

E2F-7: a distinctive E2F family member with an unusual organization of DNA-binding domains.

The E2F family of transcription factors play an important role in regulating cell cycle progression. We report here the characterization and functional properties of a new member of the human E2F family, referred to as E2F-7. E2F-7 has two separate DNA-binding domains, a feature that distinguishes E2F-7 from other mammalian E2F proteins, but resembling the organization of recently isolated E2F-like proteins from Arabidopsis. E2F-7 binds to DNA independently of a DP partner and delays cell cycle progression. Interestingly, E2F-7 modulates the transcription properties of other E2F proteins. A mutational analysis indicates that the integrity of both DNA-binding domains is required for cell cycle delay and transcriptional modulation. Biochemical results and protein modelling studies suggest that in binding to DNA interactions occur between the two DNA-binding domains, most probably as a homodimer, thereby mimicking the organization of an E2F/DP heterodimer. These structural and functional properties of E2F-7 imply a unique role in regulating cellular proliferation.

Amino Acid Motifs↗
PubMed2004

Histone deacetylase inhibitors in psoriasis therapy.

Psoriasis is recognised as a multifactorial disease with inflammatory, proliferative, angiogenic and genetic components contributing to the pathology. The disease, which may vary in intensity, remains clinically unmet although there have been several recent advances that have had a substantial impact on suffering. Histone deacetylase inhibitors represent a new class of therapeutic agent, initially developed for oncology, which prevent cell proliferation and induce differentiation. Here we discuss the possible application of HDAC inhibitors to psoriasis, focussing particularly on their anti-proliferative and anti-inflammatory activity. Our view, based upon the emerging clinical properties of HDAC inhibitors, reflects the growing recognition that HDAC inhibitors will be important therapeutic agents in diseases other than cancer.

Enzyme Inhibitors↗
PubMed2003

The cell cycle, chromatin and cancer: mechanism-based therapeutics come of age.

Tumour cells grow and divide in an uncontrolled fashion. Recent advances in the cell cycle have uncovered new mechanisms that integrate growth and division with chromatin and gene expression control. Small-molecule drugs that target key enzyme classes involved in these pathways, the cyclin-dependent kinases (Cdk) in the cell cycle and histone deacetylases (HDAC) in chromatin control, have entered clinical studies, with emerging clinical efficacy. These new mechanism-based approaches could provide significant improvements over many current chemotherapeutics.

Animals↗
PubMed2003

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.

Animals↗
PubMed2003

Chk2 activates E2F-1 in response to DNA damage.

The E2F-1 transcription factor is regulated during cell cycle progression and induced by cellular stress, such as DNA damage. We report that checkpoint kinase 2 (Chk2) regulates E2F-1 activity in response to the DNA-damaging agent etoposide. A Chk2 consensus phosphorylation site in E2F-1 is phosphorylated in response to DNA damage, resulting in protein stabilization, increased half-life, transcriptional activation and localization of phosphorylated E2F-1 to discrete nuclear structures. Expression of a dominant-negative Chk2 mutant blocks induction of E2F-1 and prevents E2F-1-dependent apoptosis. Moreover, E2F-1 is resistant to induction by etoposide in tumour cells expressing mutant chk2. Therefore, Chk2 phosphorylates and activates E2F-1 in response to DNA damage, resulting in apoptosis. These results suggest a role for E2F-1 in checkpoint control and provide a plausible explanation for the tumour suppressor activity of E2F-1.

Apoptosis↗