HES1 in immunity and cancer

Hairy and enhancer of split homolog-1 (HES1) is a part of an extensive family of basic helix-loop-helix (bHLH) proteins and plays a crucial role in the control and regulation of cell cycle, proliferation, cell differentiation, survival and apoptosis in neuronal, endocrine, T-lymphocyte progenitors as well as various cancers. HES1 is a transcription factor which is regulated by the NOTCH, Hedgehog and Wnt signalling pathways. Aberrant expression of these pathways is a common feature of cancerous cells. There appears to be a fine and complicated crosstalk at the molecular level between the various signalling pathways and HES1, which contributes to its effects on the immune response and cancers such as leukaemia. Several mechanisms have been proposed, including an enhanced invasiveness and metastasis by inducing epithelial mesenchymal transition (EMT), in addition to its strict requirement for tumour cell survival. In this review, we summarize the current biology and molecular mechanisms as well as its use as a clinical target in cancer therapeutics.

Studies of the role of nf-κb in controlling osteoclast differentiation and bone loss

Increased osteoclast (OC) bone resorption and/or decreased osteoblast (OB) bone formation contribute to bone loss in osteoporosis and rheumatoid arthritis (RA). Findings of the basic and translational research presented in this thesis demonstrate a number of mechanisms by which cytokine-induced NF-κB activation controls bone resorption and formation: 1) Tumour necrosis factor-α (TNF) expands pool of OC precursors (OCPs) by promoting their proliferation through stimulation of the expression of macrophage colony stimulating factor (M-CSF) receptor, c-Fms, and switching M-CSF-induced resident (M2) to inflammatory (M1) macrophages with enhanced OC forming potential and increased production of inflammatory factors through induction of NF-κB RelB; 2) Similar to RANKL, TNF sequentially activates transcriptional factors NF-κB p50 and p52 followed by c-Fos and then NFATc1 to induce OC differentiation. However, TNF alone induces very limited OC differentiation. In contrast, it pre-activates OCPs to express cFos which cooperates with interleukin-1 (IL-1) produced by these OCPs in an autocrine mechanism by interacting with bone matrix to mediate the OC terminal differentiation and bone resorption from these pre-activated OCPs. 3) TNF-induced OC formation is independent of RANKL but it also induces NF-κB2 p100 to limit OC formation and bone resorption, and thus p100 deletion accelerates joint destruction and systemic bone loss in TNF-induced RA; 4) TNF receptor associated factor-3 (TRAF3) limits OC differentiation by negatively regulating non-canonical NF-κB activation and RANKL induces TRAF3 ubiquitination and lysosomal degradation to promote OC differentiation. Importantly, a lysosomal inhibitor that inhibits TRAF3 degradation prevents ovariectomy-induced bone loss; 5) RelB and Notch NICD bind RUNX2 to inhibit OB differentiation and RelB:p52 dimer association with NICD inhibit OB differentiation by enhancing the binding of RBPjκ to Hes1. These findings suggest that non-canonical NF- κB signaling could be targets to develop new therapies for RA or osteoporosis. For example 1) Agents that degrade TNF-induced RelB could block M1 macrophage differentiation to inhibit inflammation and joint destruction for the therapy of RA; 2)Agents that prevent p100 processing or TRAF3 degradation could inhibit bone resorption and also stimulate bone formation simultaneously for the therapy of osteoporosis.