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Abstract Effective therapeutic targets and early diagnosis are major challenges in the treatment of gastrointestinal tract (GIT) cancers. SALL4 is a well-known transcription factor that is involved in organogenesis during embryonic development. Previous studies have revealed that SALL4 regulates cell proliferation, survival, and migration and maintains stem cell function in mature cells. Additionally, SALL4 overexpression is associated with tumorigenesis. Despite its characterization as a biomarker in various cancers, the role of SALL4 in GIT cancers and the underlying mechanisms are unclear. We describe the functions of SALL4 in GIT cancers and discuss its upstream/downstream genes and pathways associated with each cancer. We also consider the possibility of targeting these genes or pathways as potential therapeutic options for GIT cancers.

Effective therapeutic targets and early diagnosis are major challenges in the treatment of gastrointestinal tract (GIT) cancers. SALL4 is a well-known transcription factor that is involved in organogenesis during embryonic development. Previous studies have revealed that SALL4 regulates cell proliferation, survival, and migration and maintains stem cell function in mature cells. Additionally, SALL4 overexpression is associated with tumorigenesis. Despite its characterization as a biomarker in various cancers, the role of SALL4 in GIT cancers and the underlying mechanisms are unclear. We describe the functions of SALL4 in GIT cancers and discuss its upstream/downstream genes and pathways associated with each cancer. We also consider the possibility of targeting these genes or pathways as potential therapeutic options for GIT cancers. [ABSTRACT FROM AUTHOR]

Soil salinity is one of the major factors that limit the area of cultivable land and yield potential of crops. The ability of salt tolerance varies with plant species. Peanut (Arachis hypogaea L.) is a moderately salt-sensitive and economically important crop, however, their biological processes involved in salt-stress response remain unclear. In this study, we investigated the role of A. hypogaea L. ABSCISIC ACID INSENSITIVE 4s (AhABI4s) in salt tolerance and elucidated its mode of action in peanuts. The results showed that the downregulation of AhABI4 s via whole plant virus-induced gene silencing has enhanced the survival rate, biomass accumulation, and root/shoot ratio of peanut seedlings in response to salt-stress. Transcriptomics, quantitative proteomics, and phosphoproteomic analyses were performed using AhABI4 s-silenced and Mock plants. The expression pattern of 15,247 genes, 1,900 proteins, and 2,620 phosphorylation sites were affected by silencing of AhABI4 s in peanut leaf and root after sodium chloride (NaCl) treatment. Among them, 63 potential downstream target genes of ABI4 changed consistently at both transcription and translation levels, and the protein/phosphorylation levels of 31 ion transporters/channels were also affected. Electrophoretic mobility shift assays (EMSA) showed that ABI4 was able to bind to the promoters of HSP70, fructokinase (FRK), and pyruvate kinase (PK) coding genes in vitro. In addition, we also detected a binding preference of AhABI4 for CACT(G/T)GCA motif in the promoters of down-regulated genes in peanut leaf. Collectively, the potential downstream targets which were regulated at the levels of transcription and translation, binding preference, and in vivo phosphorylation sites that had been revealed in this study will provide new insight into the AhABI4s -mediated salt tolerance regulation mechanism in peanuts. [ABSTRACT FROM AUTHOR]

Soil salinity is one of the major factors that limit the area of cultivable land and yield potential of crops. The ability of salt tolerance varies with plant species. Peanut (Arachis hypogaea L.) is a moderately salt-sensitive and economically important crop, however, their biological processes involved in salt-stress response remain unclear. In this study, we investigated the role of A. hypogaea L. ABSCISIC ACID INSENSITIVE 4s (AhABI4s) in salt tolerance and elucidated its mode of action in peanuts. The results showed that the downregulation of AhABI4s via whole plant virus-induced gene silencing has enhanced the survival rate, biomass accumulation, and root/shoot ratio of peanut seedlings in response to salt-stress. Transcriptomics, quantitative proteomics, and phosphoproteomic analyses were performed using AhABI4s-silenced and Mock plants. The expression pattern of 15,247 genes, 1,900 proteins, and 2,620 phosphorylation sites were affected by silencing of AhABI4s in peanut leaf and root after sodium chloride (NaCl) treatment. Among them, 63 potential downstream target genes of ABI4 changed consistently at both transcription and translation levels, and the protein/phosphorylation levels of 31 ion transporters/channels were also affected. Electrophoretic mobility shift assays (EMSA) showed that ABI4 was able to bind to the promoters of HSP70, fructokinase (FRK), and pyruvate kinase (PK) coding genes in vitro. In addition, we also detected a binding preference of AhABI4 for CACT(G/T)GCA motif in the promoters of down-regulated genes in peanut leaf. Collectively, the potential downstream targets which were regulated at the levels of transcription and translation, binding preference, and in vivo phosphorylation sites that had been revealed in this study will provide new insight into the AhABI4s-mediated salt tolerance regulation mechanism in peanuts.

OBJECTIVE: Peroxisome proliferator-activated receptor γ (PPARγ) regulates fatty acid storage and glucose metabolism. Recently, PPARγ has been reported to be involved in cancer. The present study reported a PPARγ consensus binding site (AGGTCA) in the ptprf promoter and identified a strong association between PPARγ and PTPRF expression, as well as their tumor suppressor roles in a v-Ha-Ras-induced model of breast cancer. MATERIALS AND METHODS: The prognostic potential of PPARγ was assessed with a KM analysis of raw data from 3,951 breast cancer patients. The expression of PPARγ and PTPRF in the rat breast cancer cell lines was detected by Western blot and qPCR. The impact of PPARγ on cancer cell migration, invasion, and growth was confirmed using cell migration assay, transwell cell invasion assay, tri-dimensional soft agar culture, respectively. The binding of PPARγ with the ptprf promoter was then examined using electrophoretic mobility shift assay. The inhibitory effect of PPARγ on tumor growth was then examined in mouse tumor model in vivo. RESULTS: It was identified that PPARγ expression is lost in the aggressive v-Ha-Ras-induced breast cancer cell line FE1.2 but highly expressed in less malignant FE1.3 cells. Exogenous expression of PPARγ in FE1.2 cells (FE1.2-PPARγhi) resulted in a marked inhibition of proliferation compared with that in FE1.2-Vector control group. FE1.2-PPARγhi cells also exhibited reduced migration, invasion, and colony formation abilities compared with those of the controls. The PPARγ agonist rosiglitazone also suppressed the malignant properties of FE1.2 cells. Protein tyrosine phosphatase receptor F (PTPRF), a downstream target of PPARγ, was markedly induced in FE1.2- PPARγhi cells. A PPARγ consensus binding site (AGGTCA) was identified in the ptprf promoter, and an electrophoretic mobility shift assay confirmed that PPARγ bind to this promoter. Similar to the effect of vector-mediated overexpression of PPARγ, ectopic overexpression of PTPRF in FE1.2 cells led to reduced proliferation. Furthermore, a PPARγ antagonist (GW9662) and PTP inhibitor (NSC87877) abrogated the suppressive function of PPARγ and PTPRF in FE1.2 cells, respectively. PPARγ overexpression or activation suppressed the progression and distant organ metastasis of breast cancer cells in a NOD/SCID mouse model. CONCLUSIONS: These results suggest that PPARγ inhibits tumor cell proliferation, at least in part, through direct regulation of the ptprf gene and that PPARγ is a potential target for breast cancer treatment. [ABSTRACT FROM AUTHOR]

The maintenance of germline stem cells (GSCs) is essential for tissue homeostasis. JAK/STAT signaling maintains GSC fate in Drosophila testis. However, how JAK/STAT signaling maintains male GSC fate through its downstream targets remains poorly understood. Here, we identify p115, a tER/cis-Golgi golgin protein, as a putative downstream target of JAK/STAT signaling. p115 maintains GSC fate independent of GM130 and GRASP65. p115 localizes in cytosol, the ER and Golgi apparatus in germline cells and is required for the morphology of the ER and Golgi apparatus. Furthermore, depletion of p115 in GSCs results in aberrant spindle orientation. Mechanistically, p115 associates with and stabilizes STAT. Finally, ectopic expression of STAT completely restores GSC loss caused by p115 depletion. Collectively, JAK/STAT signaling and p115 form a feedforward loop to maintain male GSC fate. Our work provides new insights into the regulatory mechanism of how stem cell maintenance is properly controlled by JAK/STAT signaling., Competing Interests: Conflict of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

The Pax6 transcription factor is essential for development of the brain, eye, olfactory and endocrine systems. Haploinsufficiency of PAX6 in humans and mice causes the congenital condition aniridia, with defects in each of these organs and systems. Identification of the PAX6 transcription networks driving normal development is therefore critical in understanding the pathophysiology observed with loss-of-function defects. Here we have focused on identification of the downstream targets for Pax6 in the developing iris and ciliary body, where we used laser capture microdissection in mouse eyes from E12.5–E16.5, followed by chromatin immunoprecipitation, promoter-reporter assays and immunohistochemistry. We identified 6 differentially expressed genes between wildtype and Pax6 heterozygous mouse tissues and demonstrated that Bmp4 , Tgfβ2 , and Foxc1 were direct downstream targets of Pax6 in developing iris/ciliary body. These results improve our understanding of how mutations in Bmp4 , Tgfβ2 , and Foxc1 result in phenocopies of the aniridic eye disease and provide possible targets for therapeutic intervention. [ABSTRACT FROM AUTHOR]

Despite the existence of a large body of information on the subject, the mechanisms of morphine tolerance and dependence are not yet fully understood. There is substantial evidence indicating that mitogen-activated protein kinase (MAPK), a family including extracellular signal-regulated protein kinase, p38 MAPK, and c-Jun N-terminal kinase, can be activated by chronic morphine treatment in the central and peripheral nervous systems and that application of a MAPK inhibitor reduces morphine tolerance and dependence. While the exact mechanism is not completely understood, recent evidence suggests that the activation of MAPK induced by long-term morphine exposure may participate in tolerance and dependence by regulating the downstream targets, such as calcitonin gene-related peptide, substance P, nitric oxide, transient receptor potential vanilloid 1, and proinflammatory cytokines. In this review, we focus on the current understanding of the role of MAPK signaling pathways in morphine tolerance and dependence. [ABSTRACT FROM AUTHOR]