Biomedical subjects

Jun-Li Luo

Publications and source records attributed to Jun-Li Luo.

11 recordsLinked to original sources

PubMed2025

Rewiring tumor immunity via zinc finger proteins: a new frontier in cancer immunotherapy.

BACKGROUND: Zinc finger proteins (ZFPs) represent the largest and most structurally diverse family of transcription factors in the human genome. They function through characteristic zinc finger domains that enable specific binding to DNA, RNA, and proteins, playing a central regulatory role in the tumor immune microenvironment. MAIN BODY: This review systematically examines the dual functions of ZFPs in dynamically regulating both innate and adaptive immune responses in cancer. At the innate immunity level, ZFPs precisely control dendritic cell (DC) fate determination, dictate macrophage polarization, balance natural killer (NK) cell activation, mediate myeloid-derived suppressor cell (MDSC) immunosuppressive function, and modulate innate immune sensors and inflammasomes. Within adaptive immunity, ZFPs critically influence T cell effector function and regulate B cell differentiation. Building on these, diverse immunotherapeutic strategies targeting ZFPs are now emerging. These include gene-editing, small molecules and proteolysis-targeting chimeras (PROTACs), synergistic combinations with immune checkpoint blockade, and ZFP-engineered chimeric antigen receptor T (CAR-T) cells. CONCLUSIONS: As pivotal nodes within the tumor immune regulatory network, ZFP-targeting strategies offer novel opportunities to overcome current therapeutic bottlenecks.

Humans↗

PubMed2006

Convergence of Itch-induced ubiquitination with MEKK1-JNK signaling in Th2 tolerance and airway inflammation.

The immune system is capable of mounting robust responses against invading pathogens but refrains from attacking self. Many studies have focused on tolerance induction of Th1 cells, whose failure results in development of autoimmune diseases. However, the molecular mechanisms governing tolerance induction in Th2 cells and its relation to allergic responses remain unclear. Here we used both in vivo and in vitro protocols to demonstrate that Th2 cells either containing a mitogen and extracellular kinase kinase 1 (MEKK1) mutant or lacking JNK1 or the E3 ubiquitin ligase Itch cannot be tolerized. In a mouse allergic model, injection of high-dose tolerizing antigen failed to block the development of airway inflammation in Itch-/- mice. This study suggests that MEKK1-JNK signaling regulates Itch E3 ligase-mediated tolerogenic process in Th2 cells. These findings have therapeutic implications for allergic diseases.

Animals↗

PubMed2006

The E3 ubiquitin ligase itch couples JNK activation to TNFalpha-induced cell death by inducing c-FLIP(L) turnover.

The proinflammatory cytokine tumor necrosis factor (TNF) alpha signals both cell survival and death. The biological outcome of TNFalpha treatment is determined by the balance between NF-kappaB and Jun kinase (JNK) signaling; NF-kappaB promotes survival, whereas JNK enhances cell death. Critically, identity of a JNK substrate that promotes TNFalpha-induced apoptosis has been outstanding. Here we show that TNFalpha-mediated JNK activation accelerates turnover of the NF-kappaB-induced antiapoptotic protein c-FLIP, an inhibitor of caspase-8. This is not due to direct c-FLIP phosphorylation but depends on JNK-mediated phosphorylation and activation of the E3 ubiquitin ligase Itch, which specifically ubiquitinates c-FLIP and induces its proteasomal degradation. JNK1 or Itch deficiency or treatment with a JNK inhibitor renders mice resistant in three distinct models of TNFalpha-induced acute liver failure, and cells from these mice do not display inducible c-FLIP(L) ubiquitination and degradation. Thus, JNK antagonizes NF-kappaB during TNFalpha signaling by promoting the proteasomal elimination of c-FLIP(L).

Animals↗

PubMed2005

IKKbeta couples hepatocyte death to cytokine-driven compensatory proliferation that promotes chemical hepatocarcinogenesis.

IkappaB kinase beta (IKKbeta), required for NF-kappaB activation, links chronic inflammation with carcinogenesis. We investigated whether IKKbeta is involved in chemically induced liver cancer, a model not involving overt inflammation. Surprisingly, mice lacking IKKbeta only in hepatocytes (Ikkbeta(Deltahep) mice) exhibited a marked increase in hepatocarcinogenesis caused by diethylnitrosamine (DEN). This correlated with enhanced reactive oxygen species (ROS) production, increased JNK activation, and hepatocyte death, giving rise to augmented compensatory proliferation of surviving hepatocytes. Brief oral administration of an antioxidant around the time of DEN exposure blocked prolonged JNK activation and compensatory proliferation and prevented excessive DEN-induced carcinogenesis in Ikkbeta(Deltahep) mice. Decreased hepatocarcinogenesis was also found in mice lacking IKKbeta in both hepatocytes and hematopoietic-derived Kupffer cells. These mice exhibited reduced hepatocyte regeneration and diminished induction of hepatomitogens, which were unaltered in Ikkbeta(Deltahep) mice. IKKbeta, therefore, orchestrates inflammatory crosstalk between hepatocytes and hematopoietic-derived cells that promotes chemical hepatocarcinogenesis.

Animals↗

PubMed2005

The anti-death machinery in IKK/NF-kappaB signaling.

The most extensively studied function of NF-kappaB is its ability to promote cell survival through induction of target genes, whose products inhibit various aspects of the apoptotic machinery in both normal and malignant cells. Recent studies, however, indicate that NF-kappaB activation can also suppress programmed necrosis through induction of genes encoding anti-oxidant proteins. Since tumor cells often use NF-kappaB pathway as a shield to escape the killing of conventional anti-cancer therapies, intervention of IKK/NF-kappaB signaling would be a promising option to improve the efficacy of cancer treatment.

Animals↗

PubMed2005

IKK/NF-kappaB signaling: balancing life and death--a new approach to cancer therapy.

IkappaB kinase/NF-kappaB (IKK/NF-kappaB) signaling pathways play critical roles in a variety of physiological and pathological processes. One function of NF-kappaB is promotion of cell survival through induction of target genes, whose products inhibit components of the apoptotic machinery in normal and cancerous cells. NF-kappaB can also prevent programmed necrosis by inducing genes encoding antioxidant proteins. Regardless of mechanism, many cancer cells, of either epithelial or hematopoietic origin, use NF-kappaB to achieve resistance to anticancer drugs, radiation, and death cytokines. Hence, inhibition of IKK-driven NF-kappaB activation offers a strategy for treatment of different malignancies and can convert inflammation-induced tumor growth to inflammation-induced tumor regression.

Animals↗

PubMed2004

p53 designer genes for the modern mouse.

Major efforts are underway to develop molecular strategies that target the p53 pathway for the treatment of cancer. Mouse strains with humanized p53 sequences that present the precise human DNA-binding domain as mutation target could be informative models to test p53 rescue drugs, and to explore experimentally the causes of human tumor mutations.

Animals↗

PubMed2004

The protein kinase PKR is required for macrophage apoptosis after activation of Toll-like receptor 4.

Macrophages are pivotal constituents of the innate immune system, vital for recognition and elimination of microbial pathogens. Macrophages use Toll-like receptors (TLRs) to detect pathogen-associated molecular patterns--including bacterial cell wall components, such as lipopolysaccharide or lipoteichoic acid, and viral nucleic acids, such as double-stranded (ds)RNA--and in turn activate effector functions, including anti-apoptotic signalling pathways. Certain pathogens, however, such as Salmonella spp., Shigellae spp. and Yersiniae spp., use specialized virulence factors to overcome these protective responses and induce macrophage apoptosis. We found that the anthrax bacterium, Bacillus anthracis, selectively induces apoptosis of activated macrophages through its lethal toxin, which prevents activation of the anti-apoptotic p38 mitogen-activated protein kinase. We now demonstrate that macrophage apoptosis by three different bacterial pathogens depends on activation of TLR4. Dissection of anti- and pro-apoptotic signalling events triggered by TLR4 identified the dsRNA responsive protein kinase PKR as a critical mediator of pathogen-induced macrophage apoptosis. The pro-apoptotic actions of PKR are mediated both through inhibition of protein synthesis and activation of interferon response factor 3.

Animals↗

PubMed2004

Inhibition of NF-kappaB in cancer cells converts inflammation- induced tumor growth mediated by TNFalpha to TRAIL-mediated tumor regression.

We used an experimental murine cancer metastasis model in which a colon adenocarcinoma cell line generates lung metastases, whose growth is stimulated in response to injection of bacterial lipopolysaccharide (LPS), to investigate the role of NF-kappaB in inflammation-induced tumor growth. We found that LPS-induced metastatic growth response in this model depends on both TNFalpha production by host hematopoietic cells and NF-kappaB activation in tumor cells. Inhibition of NF-kappaB in both colon and mammary carcinoma cells converts the LPS-induced growth response to LPS-induced tumor regression. The latter response is TNFalpha-independent, but depends on another member of the TNF superfamily, TRAIL, whose receptor is induced in NF-kappaB-deficient cancer cells.

Adenocarcinoma↗

PubMed2003

IKKbeta is required for prevention of apoptosis mediated by cell-bound but not by circulating TNFalpha.

IkappaB kinase beta (IKKbeta) is required for NF-kappaB activation and suppression of TNFalpha-mediated liver apoptosis. To investigate how IKKbeta suppresses apoptosis, we generated hepatocyte-specific Ikkbeta knockout mice, Ikkbeta(Deltahep), which exhibit little residual NF- kappaB activity but are healthy with normal liver function. Unexpectedly, Ikkbeta(Deltahep) mice are slightly more sensitive than controls to LPS-induced liver apoptosis but are highly susceptible to liver destruction following concanavalin A (ConA)-induced T cell activation. Unlike LPS, a potent inducer of circulating TNFalpha, ConA exerts cytotoxic effects through cell-bound TNFalpha, which activates type 1 and 2 TNF receptors (TNFR). While TNFR2 does not contribute to NF-kappaB activation, it is important for ConA-induced JNK activation, which is augmented by the absence of IKKbeta. Using JNK-deficient mice we show that JNK is required for ConA-induced liver damage. Thus, the antiapoptotic function of IKKbeta, which is most critical in situations that involve cell-bound TNFalpha, is mediated partially through attenuation of JNK activity.

Animals↗

PubMed2002

Mouse models for generating P53 gene mutation spectra.

The p53 tumor suppressor gene lends itself to mutation spectra analysis, because the frequency of point mutations in human tumors is high, the locations of inactivating tumor mutations are numerous and dispersed, and all possible base substitutions are observed in human cancer. P53 tumor mutations induced experimentally in mice exposed to carcinogens have been described, but have not yet contributed significantly to our understanding of mutagenic mechanisms or of the origins of mutations in human cancers. Recently, gene-targeting technology has allowed development of a new mouse model, which explores experimentally the endogenous and environmental factors that may contribute to neoplastic disease in humans.

Animals↗