SALL4 in gastrointestinal tract cancers: upstream and downstream regulatory mechanisms.

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.

Genome-wide analysis of the KNOX gene family in Moso bamboo: insights into their role in promoting the rapid shoot growth.

BACKGROUND: KNOTTED1-like homeobox (KNOX) genes, plant-specific homologous box transcription factors (TFs), play a central role in regulating plant growth, development, organ formation, and response to biotic and abiotic stresses. However, a comprehensive genome-wide identification of the KNOX genes in Moso bamboo (Phyllostachys edulis), the fastest growing plant, has not yet been conducted, and the specific biological functions of this family remain unknown. RESULTS: The expression profiles of 24 KNOX genes, divided into two subfamilies, were determined by integrating Moso bamboo genome and its transcriptional data. The KNOX gene promoters were found to contain several light and stress-related cis-acting elements. Synteny analysis revealed stronger similarity with rice KNOX genes than with Arabidopsis KNOX genes. Additionally, several conserved structural domains and motifs were identified in the KNOX proteins. The expansion of the KNOX gene family was primarily regulated by tandem duplications. Furthermore, the KNOX genes were responsive to naphthaleneacetic acid (NAA) and gibberellin (GA) hormones, exhibiting distinct temporal expression patterns in four different organs of Moso bamboo. Short Time-series Expression Miner (STEM) analysis and quantitative real-time PCR (qRT-PCR) assays demonstrated that PeKNOX genes may play a role in promoting rapid shoot growth. Additionally, Gene Ontology (GO) and Protein-Protein Interaction (PPI) network enrichment analyses revealed several functional annotations for PeKNOXs. By regulating downstream target genes, PeKNOXs are involved in the synthesis of AUX /IAA, ultimately affecting cell division and elongation. CONCLUSIONS: In the present study, we identified and characterized a total of 24 KNOX genes in Moso bamboo and investigated their physiological properties and conserved structural domains. To understand their functional roles, we conducted an analysis of gene expression profiles using STEM and RNA-seq data. This analysis successfully revealed regulatory networks of the KNOX genes, involving both upstream and downstream genes. Furthermore, the KNOX genes are involved in the AUX/IAA metabolic pathway, which accelerates shoot growth by influencing downstream target genes. These results provide a theoretical foundation for studying the molecular mechanisms underlying the rapid growth and establish the groundwork for future research into the functions and transcriptional regulatory networks of the KNOX gene family.

A feedforward loop between JAK/STAT downstream target p115 and STAT in germline stem cells.

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.

A patent review of MAPK inhibitors (2018 - present).

INTRODUCTION: The mitogen-activated protein kinase (MAPK) family consist of p38 MAP kinases, c-Jun N-terminal kinases (JNKs) and extracellular signal-regulated kinases (ERKs). They are involved in a multitude of diseases, including inflammatory, autoimmune, neurodegenerative, and metabolic diseases as well as cancer. In recent years, further developments in the field of MAPK-inhibitors have been reported, including an isoform or downstream target selective inhibition of MAPKs as well as target protein degradation approaches. AREAS COVERED: This review summarizes newly patented MAPK-inhibitors that were claimed between 2018 and early 2023. Presented are the patents as well as their corresponding publications, the storyline of development, and clinical trials involving these compounds. This article elaborates a total of 27 patents, which were identified using established search engines. EXPERT OPINION: Although industrial research on MAPK-inhibitors has been ongoing for more than 20 years, novel clinical trials of MAPK-inhibitors as potential drug candidates are still being conducted in the period under review. Recently reported inhibitors show an excellent selectivity profile and are even achieving selectivity between closely related isoforms. This progression offers the possibility to eliminate unwanted side effects and may finally lead to the approval of the first MAPK-inhibitor.

LncRNA FGD5-AS1 Promotes Abdominal Aortic Aneurysm Growth Through the Activation of MMP3 in Vascular Smooth Muscle Cells.

Long noncoding RNAs (lncRNAs) can serve as treatment targets for abdominal aortic aneurysms (AAAs). Nonetheless, the exact role of FGD5 antisense RNA 1 (FGD5-AS1) in AAAs is unclear. Therefore, this study investigated the contribution of FGD5-AS1 to AAA growth regulated by vascular smooth muscle cells (VSMCs) and its potential mechanisms. ApoE-/- mice were used to establish the angiotensin II (Ang II)-elicited AAA model. RNA pull-down assay and dual luciferase reporter assay (DLRA) in human VSMCs were used in examining the interactions between FGD5-AS1 and its downstream proteins or miRNA targets. FGD5-AS1 expression in the mouse Ang II perfusion group was dramatically increased relative to the PBS-infused group. In the mouse AAA model, FGD5-AS1 overexpression induced SMC apoptosis, thereby promoting AAA growth. miR-195-5p acts as a potential FGD5-AS1 downstream target, whereas FGD5-AS1 promotes MMP3 expression by inhibiting miR-195-5p expression, thereby inhibiting proliferation and promoting apoptosis of smooth muscle cells. LncRNA FGD5-AS1 is detrimental to the proliferation and survival of SMCs during AAA growth. Therefore, FGD5-AS1 could be a novel treatment target for AAA.

Transcription factor ZmWRKY20 interacts with ZmWRKY115 to repress expression of ZmbZIP111 for salt tolerance in maize.

Maize (Zea mays) is an important cereal crop worldwide. However, its yield and quality are adversely affected by salt stress resulting from soil hypersalinity. Exploring the regulatory mechanisms of stress responses is of vital importance to increase maize seed production. In the present study, we screened ethyl methanesulfonate-induced maize mutants and identified a salt-tolerant mutant. A single base was mutated in ZmWRKY20, leading to the formation of a truncated protein variant. A detailed phenotypic analysis revealed that this mutant had significantly higher resistance to wilting and lower reactive oxygen species levels than the inbred line B73. ZmWRKY20 showed transcriptional activity in yeast and specifically bound W-boxes according to the results of our yeast one-hybrid, electrophoretic mobility shift, and dual-luciferase assays. Overexpression of ZmWRKY20 decreased salt tolerance in maize. Transcriptome profiling revealed that ZmWRKY20 overexpression extensively reprogrammed genes involved in regulating defense and oxidation-reduction responses. The results substantiate that ZmWRKY20 is directly targeted to the basic leucine zipper (bZIP) motif in the transcription factor ZmbZIP111. It was also verified that ZmWRKY20 interacts with ZmWRKY115 and both proteins act jointly to enhance ZmbZIP111 repression. The results indicate that the ZmWRKY20 and ZmWRKY115 transcription factors interact in the nucleus, leading to repression of ZmbZIP111 expression by directly binding its promoter, and increase the sensitivity of maize seedlings to salt stress. The current study improves our understanding of the complicated responses of maize to salt stress.

AhABI4s Negatively Regulate Salt-Stress Response in Peanut.

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.

A mouse model of aniridia reveals the in vivo downstream targets of Pax6 driving iris and ciliary body development in the eye.

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, Tgfß2, and Foxc1 were direct downstream targets of Pax6 in developing iris/ciliary body. These results improve our understanding of how mutations in Bmp4, Tgfß2, and Foxc1 result in phenocopies of the aniridic eye disease and provide possible targets for therapeutic intervention.

Hesx1 enhances pluripotency by working downstream of multiple pluripotency-associated signaling pathways.

Hesx1, a homeobox gene expressed in embryonic stem cells (ESCs), has been implicated in the core transcription factors governing the pluripotent state. However, data about the underlying mechanism of how Hesx1 is involved in maintaining pluripotency is still scarce. In this study, we find Hesx1 responds to multiple pluripotency-related pathway inhibitors as well as LIF stimulation. Particularly, the expression of Hesx1 can be readily induced by dual inhibition (2i) of glycogen synthase kinase 3 and mitogen-activated protein kinase. Forced expression of Hesx1 can partially compensate for the withdrawal of either LIF or each component of 2i. We also demonstrate that LIF and each inhibitor of 2i can induce Hesx1 independent of one another. We tentatively put forward that Hesx1 is a common downstream target of LIF- and 2i-mediated self-renewal signaling pathways and plays an important role in maintaining ESC identity. Our study extends the methods of identifying the missing crucial factors in establishing ESC pluripotency.