Targeted inhibition of Snail family zinc finger transcription factors by oligonucleotide-Co(III) Schiff base conjugate

Harney, Allison S.; Lee, Jiyoun; Manus, Lisa M.; Wang, Peijiao; Ballweg, David; LaBonne, Carole; Meade, Thomas J.

doi:10.1073/pnas.0906423106

Cited by 78 publications

(98 citation statements)

References 40 publications

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“…Nevertheless, our findings document a required role for endogenous hepatocyte Snail1 in the evolution of liver fibrosis independent of the magnitude of the hepatocyte EMT program per se. The functional importance of endogenously derived Snail1 documented in this study, coupled with recent progress in developing new therapeutics designed to block Snail1 activity in vivo (18), underscores the importance of extending these observations to other disease models.…”

Section: Discussionmentioning

confidence: 99%

Hepatocyte-Derived Snail1 Propagates Liver Fibrosis Progression

Rowe¹,

Lin²,

Shimizu–Hirota³

et al. 2011

Molecular and Cellular Biology

117

108

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Chronic exposure of the liver to hepatotoxic agents initiates an aberrant wound healing response marked by proinflammatory, as well as fibrotic, changes, leading to compromised organ structure and function. In a variety of pathological states, correlative links have been established between tissue fibrosis and the expression of transcription factors associated with the induction of epithelial-mesenchymal cell transition (EMT) programs similar to those engaged during development. However, the role played by endogenously derived, EMT-associated transcription factors in fibrotic states in vivo remains undefined. Using a mouse model of acute liver fibrosis, we demonstrate that hepatocytes upregulate the expression of the zinc finger transcriptional repressor, Snail1, during tissue remodeling. Hepatocyte-specific ablation of Snail1 demonstrates that this transcription factor plays a key role in liver fibrosis progression in vivo by triggering the proximal genetic programs that control multiple aspects of fibrogenesis, ranging from growth factor expression and extracellular matrix biosynthesis to the ensuing chronic inflammatory responses that characterize this class of pathological disorders.

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Section: Discussionmentioning

confidence: 99%

Hepatocyte-Derived Snail1 Propagates Liver Fibrosis Progression

Rowe¹,

Lin²,

Shimizu–Hirota³

et al. 2011

Molecular and Cellular Biology

117

108

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“…This places ZEB2 as one of the key regulators of effector CD8 + T cell terminal differentiation and highlights a key fate decision point in the formation of CD8 + T cell memory. The function of ZEB2 in regulating terminal differentiation of CD8 + T cells, similar to other systems (see Conidi et al [2011]), and the fact that it is a zinc-finger-containing transcription factor make it an interesting and specific therapeutic target as has been shown for other zinc-finger transcription factors, including the Snail family (Rice et al, 1997;Harney et al, 2009Harney et al, , 2012Larabee et al, 2009). Furthermore, these data help foster a basal understanding of the mechanisms of memory formation, providing insight that may inform future vaccine design.…”

Section: Discussionmentioning

confidence: 99%

Transcriptional repressor ZEB2 promotes terminal differentiation of CD8⁺ effector and memory T cell populations during infection

Omilusik¹,

Best²,

Yu³

et al. 2015

J Cell Biol

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In response to intracellular pathogens, CD8 + T cells are activated to proliferate and differentiate into a heterogeneous population of effector T cells, which are armed to eliminate infected cells. After pathogen clearance, the majority of effector CD8 + T cells die; however, a subset survives and differentiates to long-lived memory T cells. Should reinfection occur, these memory cells undergo rapid expansion and redifferentiation into effector cells, providing superior protection compared with naive T cells and protecting the host for decades in many cases (Harty and Badovinac, 2008). The ability to selectively induce T cell memory would provide novel methods for provoking protective immunity and inform vaccine strategies.Identification of effector and memory precursor CD8 + T cells within the effector population is facilitated by their distinct expression of several surface receptors. Both subsets express high levels of CD44, whereas IL-7-receptor-α (CD127) is selectively up-regulated during the transition to long-lived memory cells (Kaech et al., 2003). Killer cell lectin-like receptor G1 (KLRG1) expression is inversely correlated with CD127 expression (Joshi et al., 2007) and identifies, in both mice and humans, a subset of terminally differentiated effector cells that possess limited proliferative potential and a shorter lifespan (Voehringer et al., 2002;Joshi et al., 2007).ZEB2 is a multi-zinc-finger transcription factor known to play a significant role in early neurogenesis and in epithelial-mesenchymal transition-dependent tumor metastasis. Although the function of ZEB2 in T lymphocytes is unknown, activity of the closely related family member ZEB1 has been implicated in lymphocyte development. Here, we find that ZEB2 expression is up-regulated by activated T cells, specifically in the KLRG1 hi effector CD8 + T cell subset. Loss of ZEB2 expression results in a significant loss of antigen-specific CD8 + T cells after primary and secondary infection with a severe impairment in the generation of the KLRG1 hi effector memory cell population. We show that ZEB2, which can bind DNA at tandem, consensus E-box sites, regulates gene expression of several E-protein targets and may directly repress Il7r and Il2 in CD8 + T cells responding to infection. Furthermore, we find that T-bet binds to highly conserved T-box sites in the Zeb2 gene and that T-bet and ZEB2 regulate similar gene expression programs in effector T cells, suggesting that T-bet acts upstream and through regulation of ZEB2. Collectively, we place ZEB2 in a larger transcriptional network that is responsible for the balance between terminal differentiation and formation of memory CD8 + T cells. Thus, differential expression of CD127 and KLRG1 identifies two populations of T cells during the peak of an infection: KLRG1 hi CD127 lo cells that consist of shorter-lived effector and effector memory cells and KLRG1 lo CD127 hi effector cells that include the long-lived memory precursors (Kaech and Wherry, 2007;Kallies, 2008). Notably, both populations under...

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“…This could be explained as the following. As POM-Dawson targets the HHQK cluster of Ab 23 , and Ni and Co are well known to possess high binding affinity to histidine [24][25][26][27] Stability of POM and POMds. One issue that needs to be addressed is the stability of the POM and POMds under our experimental conditions 23 .…”

Section: Resultsmentioning

confidence: 99%

“…According to previous results, POMs target the cationic cluster from His13 to Lys16 (HHQK) on Ab 23 . Notably, this cluster contains two adjacent histidines, which can specifically chelate transition metal ions, such as Ni(II) or Co(II) [24][25][26][27] . Therefore, histidine can be a potential chelating site for POMs to improve their specific recognition of Ab.…”

mentioning

confidence: 99%

Transition-metal-substituted polyoxometalate derivatives as functional anti-amyloid agents for Alzheimer’s disease

et al. 2014

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Inhibitions of amyloid b (Ab) aggregation and Ab-haem peroxidase-like activity have received much attention because these two symptoms can be the primary targets of therapeutic strategies for Alzheimer's disease (AD). Recently, our group found that polyoxometalate (POM) with a Wells-Dawson structure can efficiently inhibit Ab aggregation. However, the interaction between POMs and Ab is robust, but still needs to improve Ab binding affinity. More importantly, it is unclear whether POMs can cross the blood-brain barrier and decrease Ab-haem peroxidase-like activity. Here we show that our designed series of transition metal-functionalized POM derivatives with a defined histidine-chelated binding site have much better Ab inhibition and peroxidase-like activity inhibition effects than the parent POM. More intriguingly, we show that these compounds can cross the blood-brain barrier and are metabolized after 48 h. Our work provides insights into the design, synthesis and screening of inorganic metal compounds as multifunctional therapeutic agents against AD.

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Targeted inhibition of Snail family zinc finger transcription factors by oligonucleotide-Co(III) Schiff base conjugate

Cited by 78 publications

References 40 publications

Hepatocyte-Derived Snail1 Propagates Liver Fibrosis Progression

Hepatocyte-Derived Snail1 Propagates Liver Fibrosis Progression

Transcriptional repressor ZEB2 promotes terminal differentiation of CD8⁺ effector and memory T cell populations during infection

Transition-metal-substituted polyoxometalate derivatives as functional anti-amyloid agents for Alzheimer’s disease

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Targeted inhibition of Snail family zinc finger transcription factors by oligonucleotide-Co(III) Schiff base conjugate

Cited by 78 publications

References 40 publications

Hepatocyte-Derived Snail1 Propagates Liver Fibrosis Progression

Hepatocyte-Derived Snail1 Propagates Liver Fibrosis Progression

Transcriptional repressor ZEB2 promotes terminal differentiation of CD8+ effector and memory T cell populations during infection

Transition-metal-substituted polyoxometalate derivatives as functional anti-amyloid agents for Alzheimer’s disease

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Transcriptional repressor ZEB2 promotes terminal differentiation of CD8⁺ effector and memory T cell populations during infection