Hedgehog Signaling: Implications in Cancers and Viral Infections

Iriana, Sidney; Asha, Kumari; Repak, Miroslava; Sharma-Walia, Neelam

doi:10.3390/ijms22031042

Cited by 48 publications

(40 citation statements)

References 301 publications

(401 reference statements)

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“…Although we did not explore this possibility, our results showed that the expression of GLI2 (only detected in HMC-1.1 and HMC-1.2 cells) is regulated by KIT oncogenic signals, mainly the MEK/ERK1/2 pathway and to some extent the PI3K pathway (Supplementary Figure 1A) suggesting positive feedback loops between KIT and GLI. The increase in GLI2 expression in the rapidly growing neoplastic HMC-1.1 and HMC-1.2 cells (Table 1 and Supplementary Figure 1) is consistent with findings that increased expression of GLI A can lead to transformation (18,19).…”

Section: Discussionsupporting

confidence: 88%

“…In the presence of HH ligands, PTCH1 stops the inhibition of SMO, proteolysis of GLI is blocked and thus active, full length GLI activator forms (GLI A ) accumulate and translocate into the nucleus to induce gene transcription. Unlike GLI2 and GLI3, GLI1 is not subject to proteolysis, and its levels are mainly regulated by induction of transcription, which is the reason why GLI1 is used as a reliable reporter of HH activity ( 18 , 19 ). Overall, GLI1 acts exclusively and GLI2 primarily as transcriptional activators (GLI A ), while GLI3 acts as the main transcriptional repressor due to its proteolytic processing ( 20 , 21 ).…”

Section: Introductionmentioning

confidence: 99%

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A Critical Function for the Transcription Factors GLI1 and GLI2 in the Proliferation and Survival of Human Mast Cells

et al. 2022

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Mast cell hyperactivity and accumulation in tissues are associated with allergy and other mast cell-related disorders. However, the molecular pathways regulating mast cell survival in homeostasis and disease are not completely understood. As glioma-associated oncogene (GLI) proteins are involved in both tissue homeostasis and in the hematopoietic system by regulating cell fate decisions, we sought to investigate the role for GLI proteins in the control of proliferation and survival of human mast cells. GLI1 transcripts were present in primary human mast cells and mast cell lines harboring or not activating mutations in the tyrosine kinase receptor KIT (HMC-1.1 and HMC-1.2, and LAD2 cells, respectively), while GLI2 transcripts were only present in HMC-1.1 and HMC-1.2 cells, suggesting a role for oncogenic KIT signaling in the regulation of GLI2. Reduction in GLI activity by small molecule inhibitors, or by shRNA-mediated knockdown of GLI1 or GLI2, led to increases in apoptotic cell death in both cultured human and murine mast cells, and reduced the number of peritoneal mast cells in mice. Although GLI proteins are typically activated via the hedgehog pathway, steady-state activation of GLI in mast cells occurred primarily via non-canonical pathways. Apoptosis induced by GLI silencing was associated with a downregulation in the expression of KIT and of genes that influence p53 stability and function including USP48, which promotes p53 degradation; and iASPP, which inhibits p53-induced transcription, thus leading to the induction of p53-regulated apoptotic genes. Furthermore, we found that GLI silencing inhibited the proliferation of neoplastic mast cell lines, an effect that was more pronounced in rapidly growing cells. Our findings support the conclusion that GLI1/2 transcription factors are critical regulators of mast cell survival and that their inhibition leads to a significant reduction in the number of mast cells in vitro and in vivo, even in cells with constitutively active KIT variants. This knowledge can potentially be applicable to reducing mast cell burden in mast cell-related diseases.

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Section: Discussionsupporting

confidence: 88%

Section: Introductionmentioning

confidence: 99%

A Critical Function for the Transcription Factors GLI1 and GLI2 in the Proliferation and Survival of Human Mast Cells

et al. 2022

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“…Hedgehog signaling pathway represents a conserved signaling mechanism that plays a critical role in embryogenesis, tissue homeostasis, smooth muscle differentiation, and cell proliferation (Iriana et al, 2021; Jeng et al, 2020; Quaglio et al, 2020). The posttranslational modifications, various transcriptional mechanisms, and nuclear cytoplasmic shuttling regulate the activity of the proteins associated with the hedgehog pathway (Sari et al, 2018).…”

Section: Anticancer Compounds Based On Anthranilic Acid Analoguesmentioning

confidence: 99%

Medicinal chemistry of anthranilic acid derivatives: A mini review

Prasher

Sharma

2021

Drug Development Research

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Anthranilic acid and its analogues present a privileged profile as pharmacophores for the rational development of pharmaceuticals deliberated for managing the pathophysiology and pathogenesis of various diseases. The substitution on anthranilic acid scaffold provides large compound libraries, which enable a comprehensive assessment of the structure activity relationship (SAR) analysis for the identification of hits and leads in a typical drug development paradigm. Besides, their widespread applications as anti‐inflammatory fenamates, the amide and anilide derivatives of anthranilic acid analogues play a central role in the management of several metabolic disorders. In addition, these derivatives of anthranilic acid exhibit interesting antimicrobial, antiviral and insecticidal properties, whereas the derivatives based on anthranilic diamide scaffold present applications as P‐glycoprotein inhibitors for managing the drug resistance in cancer cells. In addition, the anthranilic acid derivatives serve as the inducers of apoptosis, inhibitors of hedgehog signaling pathway, inhibitors of mitogen activated protein kinase pathway, and the inhibitors of aldo‐keto reductase enzymes. The antiviral derivatives of anthranilic acid focus on the inhibition of hepatitis C virus NS5B polymerase to manifest considerable antiviral properties. The anthranilic acid derivatives reportedly present neuroprotective applications by downregulating the key pathways responsible for the manifestation of neuropathological features and neurodegeneration. Nevertheless, the transition metal complexes of anthranilic acid derivatives offer therapeutic applications in diabetes mellitus, and obesity by regulating the activity of α‐glucosidase. The present review demonstrates a critical analysis of the therapeutic profile of the key derivatives of anthranilic acid and its analogues for the rational development of pharmaceuticals and therapeutic molecules.

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“…In addition to its indispensable role in developmental processes, more than 25% of all cancers require autocrine or paracrine HH signaling as a fundamental supporter of tumor cell growth and survival (Figure 1) (Lum and Beachy, 2004;Iriana et al, 2021). In EBV-positive nasopharyngeal carcinomas (NPC) and EBV-infected epithelial cell lines, the virus can activate the HH signaling pathway through autocrine induction of SHH (Port et al, 2013).…”

Section: Hh Signaling Targeted By Oncogenic Viruses Promotes Tumor Developmentmentioning

confidence: 99%

When Viruses Cross Developmental Pathways

Trivedi

Patel

Bellavia

et al. 2021

Front. Cell Dev. Biol.

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Aberrant regulation of developmental pathways plays a key role in tumorigenesis. Tumor cells differ from normal cells in their sustained proliferation, replicative immortality, resistance to cell death and growth inhibition, angiogenesis, and metastatic behavior. Often they acquire these features as a consequence of dysregulated Hedgehog, Notch, or WNT signaling pathways. Human tumor viruses affect the cancer cell hallmarks by encoding oncogenic proteins, and/or by modifying the microenvironment, as well as by conveying genomic instability to accelerate cancer development. In addition, viral immune evasion mechanisms may compromise developmental pathways to accelerate tumor growth. Viruses achieve this by influencing both coding and non-coding gene regulatory pathways. Elucidating how oncogenic viruses intersect with and modulate developmental pathways is crucial to understanding viral tumorigenesis. Many currently available antiviral therapies target viral lytic cycle replication but with low efficacy and severe side effects. A greater understanding of the cross-signaling between oncogenic viruses and developmental pathways will improve the efficacy of next-generation inhibitors and pave the way to more targeted antiviral therapies.

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Hedgehog Signaling: Implications in Cancers and Viral Infections

Cited by 48 publications

References 301 publications

A Critical Function for the Transcription Factors GLI1 and GLI2 in the Proliferation and Survival of Human Mast Cells

A Critical Function for the Transcription Factors GLI1 and GLI2 in the Proliferation and Survival of Human Mast Cells

Medicinal chemistry of anthranilic acid derivatives: A mini review

When Viruses Cross Developmental Pathways

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