Modulation Of Signal Transduction Pathways Research Articles

Stem Cell Division and Its Critical Role in Mammary Gland Development and Tumorigenesis: Current Progress and Remaining Challenges.

The origin of breast cancer (BC) has traditionally been a focus of medical research. It is widely acknowledged that BC originates from immortal mammary stem cells and that these stem cells participate in two division modes: symmetric cell division (SCD) and asymmetrical cell division (ACD). Although both of these modes are key to the process of breast development and their imbalance is closely associated with the onset of BC, the molecular mechanisms underlying these phenomena deserve in-depth exploration. In this review, we first outline the molecular mechanisms governing ACD/SCD and analyze the role of ACD/SCD in various stages of breast development. We describe that the changes in telomerase activity, the role of polar proteins, and the stimulation of ovarian hormones subsequently lead to two distinct consequences: breast development or carcinogenesis. Finally, gene mutations, abnormalities in polar proteins, modulation of signal-transduction pathways, and alterations in the microenvironment disrupt the balance of BC stem cell division modes and cause BC. Important regulatory factors such as mammalian Inscuteable mInsc, Numb, Eya1, PKCα, PKCθ, p53, and IL-6 also play significant roles in regulating pathways of ACD/SCD and may constitute key targets for future research on stem cell division, breast development, and tumor therapy.

Advances in functional studies of plant MYC transcription factors.

Myelocytomatosis (MYC) transcription factors (TFs) belong to the basic helix-loop-helix (bHLH) family in plants and play a central role in governing a wide range of physiological processes. These processes encompass plant growth, development, adaptation to biotic and abiotic stresses, as well as secondary metabolism. In recent decades, significant strides have been made in comprehending the multifaceted regulatory functions of MYCs. This advancement has been achieved through the cloning of MYCs and the characterization of plants with MYC deficiencies or overexpression, employing comprehensive genome-wide 'omics' and protein-protein interaction technologies. MYCs act as pivotal components in integrating signals from various phytohormones' transcriptional regulators to orchestrate genome-wide transcriptional reprogramming. In this review, we have compiled current research on the role of MYCs as molecular switches that modulate signal transduction pathways mediated by phytohormones and phytochromes. This comprehensive overview allows us to address lingering questions regarding the interplay of signals in response to environmental cues and developmental shift. It also sheds light on the potential implications for enhancing plant resistance to diverse biotic and abiotic stresses through genetic improvements achieved by plant breeding and synthetic biology efforts.

The Role of the MiR-181 Family in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is the fourth-leading cause of cancer-related death worldwide. Due to the high mortality rate in HCC patients, discovering and developing novel systemic treatment options for HCC is a vital unmet medical need. Among the numerous molecular alterations in HCCs, microRNAs (miRNAs) have been increasingly recognised to play critical roles in hepatocarcinogenesis. We and others have recently revealed that members of the microRNA-181 (miR-181) family were up-regulated in some, though not all, human cirrhotic and HCC tissues-this up-regulation induced epithelial-mesenchymal transition (EMT) in hepatocytes and tumour cells, promoting HCC progression. MiR-181s play crucial roles in governing the fate and function of various cells, such as endothelial cells, immune cells, and tumour cells. Previous reviews have extensively covered these aspects in detail. This review aims to give some insights into miR-181s, their targets and roles in modulating signal transduction pathways, factors regulating miR-181 expression and function, and their roles in HCC.

Abstract 2672: GD3 synthase (ST8SIA1) is a key immunomodulator in GD2+ breast cancer cells

Abstract Background: Gangliosides are acidic glycosphingolipids involved in cell adhesion, proliferation, and modulation of signal transduction pathways. It has been reported that tumor-shed gangliosides influence the activity of immune cells, including macrophages, NK cells, and T cells. GD3 synthase (GD3S) is the key enzyme that regulates the biosynthesis of the b and c-series gangliosides, particularly GD3 and GD2, and studies have shown that GD3S is upregulated in most tumors and plays a role in tumor progression. Similarly, we have found GD3S to be significantly upregulated in GD2+ breast cancer stem cells (BCSC) compared to GD2− cells, and the knockdown of this gene prevented tumor formation in mice. Here, we hypothesize that GD3 synthase has an immunomodulatory function in breast cancer (BC) cells through the upregulation of GD2. Methods: We stably overexpressed GD3S in BT549 and MCF-7 breast cancer cell lines by lentiviral transfection and performed CRISPR-Cas9 knockout of GD3S in BT549 and SUM 159 cell lines. We examined the effect of GD3 synthase on macrophage-mediated phagocytosis, NK cell-mediated killing, and T-cell cytotoxicity of BC cells using the live cell imaging system, IncuCyte®. Naxitamab is a US FDA-approved fully humanized anti-GD2 monoclonal antibody for the treatment of neuroblastoma. We evaluated the effects of naxitamab in GD2+ BC cell lines (HCC1395, Hs578T) using the Incucyte, and also examined its effect on in vivo tumor growth using TNBC PDX models. Results: We observed a highly significant decrease in macrophage-mediated phagocytosis (p<0.005; p<0.0001) and NK-mediated killing (p<0.0001; p<0.0001) in BT549 and MCF-7 cell overexpressing GD3S compared to the control cells. Interestingly, we observed a significant increase in phagocytosis in GD3S knockout BT549 and SUM 159 cells (p<0.05; p<0.005) compared to their wild-type counterparts. Moreover, the knockout of GD3S enhanced NK cell-mediated apoptosis in BT549 cells (p<0.001) and T cell killing in BT549 and SUM 159 cells (p<0.0001; p<0.0001). Finally, we found that naxitamab dose-dependently enhances macrophage-mediated phagocytosis and NK cell-mediated apoptosis in HCC1395 and Hs578T BC cells, with 20µg/ml being the most effective concentration in comparison to IgG control (p<0.0001; p<0.0001). In addition, we observed a reduction in tumor volume in naxitamab-treated mice compared to IgG control (p<0.05) Conclusion: GD3 synthase regulates macrophage-mediated phagocytosis, NK cell-induced apoptosis, and T-cell cytotoxicity in BC cells. Naxitamab enhances immune cell killing of breast cancer cells with high GD2 expression. Furthermore, naxitamab inhibited tumor growth in GD2+ TNBC PDX models. Citation Format: Bolutyfe Oderinde, Vivek Anand, Maryam Siddiqui, Anudishi Tyagi, Borgman Jenny, Venkata Lokesh Battula. GD3 synthase (ST8SIA1) is a key immunomodulator in GD2+ breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2672.

Evaluation of selected circulating cytokines from the IL-6 family - interleukin 6, oncostatin M, and cardiotrophin-1 - in gastro-entero-pancreatic and bronchial neuroendocrine tumours.

The incidence of neuroendocrine tumours (NETs) increased over the last years. Most of them are non-functioning, and the course of the disease is asymptomatic for a long time. This results in late diagnosis at an advanced stage. The aim of our study was the evaluation of selected circulating cytokines of interleukin-6 family - interleukin 6 (IL-6), oncostatin M (OSM), and cardiotrophin-1 (CT1) - in NETs. The study group comprised 80 patients (56%) in several subgroups, including gastroenteropancreatic (GEPNETs, n = 64, 80%) and bronchopulmonary neuroendocrine tumours (BPNETs, n = 16; 20%). Serum IL-6, OSM, and CT1 concentrations were tested using ELISA. The median concentration of IL-6 was 41.5 pg/ml in the study group and 32.6 pg/ml in the control group, and the difference was statistically significant (p < 0.001). The concentration of OSM was significantly lower in the study group than in the control group (p < 0.001), at 105.6 pg/ml and 115.5 pg/ml, respectively. There was a significant difference (p < 0.01) in concentration of CT1 in the study group (222.0 pg/ml) and controls (267.2 pg/ml). Our investigation into selected IL-6 family cytokines revealed differential modulation of signal transduction pathways. These findings suggest that despite utilising a common signalling transducer, individual IL-6 family cytokines exert distinct biological effects on neuroendocrine tumour development. Notably, IL-6 appears to promote tumourigenesis, while OSM and CT1 exhibit inhibitory effects on gastro-entero-pancreatic and bronchial neuroendocrine tumour development. Further studies are necessary to validate the diagnostic utility of IL-6 family cytokines in NETs.

Role of Mangiferin in Management of Cancers through Modulation of Signal Transduction Pathways.

Cancer is a major public health concern worldwide in terms of mortality. The exact reason behind the development of cancer is not understood clearly, but it is evidenced that alcohol consumption, radiation, and exposure to chemicals are main players in this pathogenesis. The current mode of treatments such as surgery, chemotherapy, and radiotherapy are effective, but, still, cancer is a major problem leading to death and other side effects. However, safer and effective treatment modules are needed to overcome the adverse effects of current treatment modules. In this regard, natural compounds have been recognized to ameliorate diseases by exerting anti-inflammatory, anti-oxidative, and anti-tumor potential through several mechanisms. Mangiferin, a xanthone C-glucoside, is found in several plant species including Mangifera indica (mango), and its role in disease prevention has been confirmed through its antioxidant and anti-inflammatory properties. Furthermore, its anti-cancer-potential mechanism has been designated through modulation of cell signaling pathways such as inflammation, angiogenesis, PI3K/AKT, apoptosis, and cell cycle. This article extensively reviews the anticancer potential of mangiferin in different cancers through the modulation of cell signaling pathways. Moreover, the synergistic effects of this compound with some commonly used anti-cancer drugs against different cancer cells are discussed. More clinical trials should be performed to reconnoiter the anti-cancer potential of this compound in human cancer treatment. Further, understanding of mechanisms of action and the safety level of this compound can help to manage diseases, including cancer.

Hesperidin, a Bioflavonoid in Cancer Therapy: A Review for a Mechanism of Action through the Modulation of Cell Signaling Pathways.

Cancer represents one of the most frequent causes of death in the world. The current therapeutic options, including radiation therapy and chemotherapy, have various adverse effects on patients' health. In this vista, the bioactive ingredient of natural products plays a vital role in disease management via the inhibition and activation of biological processes such as oxidative stress, inflammation, and cell signaling molecules. Although natural products are not a substitute for medicine, they can be effective adjuvants or a type of supporting therapy. Hesperidin, a flavonoid commonly found in citrus fruits, with its potential antioxidant, anti-inflammatory, and hepatoprotective properties, and cardio-preventive factor for disease prevention, is well-known. Furthermore, its anticancer potential has been suggested to be a promising alternative in cancer treatment or management through the modulation of signal transduction pathways, which includes apoptosis, cell cycle, angiogenesis, ERK/MAPK, signal transducer, and the activator of transcription and other cell signaling molecules. Moreover, its role in the synergistic effects with anticancer drugs and other natural compounds has been described properly. The present article describes how hesperidin affects various cancers by modulating the various cell signaling pathways.

Potential Therapeutic Targets of Formononetin, a Type of Methoxylated Isoflavone, and Its Role in Cancer Therapy through the Modulation of Signal Transduction Pathways.

Cancer is one of the main causes of death in all developed and developing countries. Various factors are involved in cancer development and progression, including inflammation and alterations in cellular processes and signaling transduction pathways. Natural compounds have shown health-promoting effects through their antioxidant and anti-inflammatory potential, having an important role in the inhibition of cancer growth. In this regard, formononetin, a type of isoflavone, plays a significant role in disease management through the modulation of inflammation, angiogenesis, cell cycle, and apoptosis. Furthermore, its role in cancer management has been proven through the regulation of different signal transduction pathways, such as the signal transducer and activator of transcription 3 (STAT 3), Phosphatidyl inositol 3 kinase/protein kinase B (PI3K/Akt), and mitogen activating protein kinase (MAPK) signaling pathways. The anticancer potential of formononetin has been reported against various cancer types, such as breast, cervical, head and neck, colon, and ovarian cancers. This review focuses on the role of formononetin in different cancer types through the modulation of various cell signaling pathways. Moreover, synergistic effect with anticancer drugs and methods to improve bioavailability are explained. Thus, detailed studies based on clinical trials are required to explore the potential role of formononetin in cancer prevention and treatment.

Obefazimod: A First-in-class Drug for the Treatment of Ulcerative Colitis.

Biologic agents and oral small molecules are the mainstays of inflammatory bowel disease [IBD] management. However, an unmet clinical need remains for additional agents with novel mechanism of action which are effective, safe, and disease-modifying; this is due to the substantial proportion of patients who do not respond, lose response, or develop intolerance to currently marketed products. microRNAs [miRNAs] that play a role in the modulation of signal transduction pathways implicated in the development of IBD hold the potential to be used as therapeutic targets. Recently, a novel first-in-class compound, obefazimod, originally conceived as a human immunodeficiency virus [HIV] infection drug, has shown great promise in phase II induction trials for ulcerative colitis [UC] patients. Findings from the maintenance phases of trials showed that long-term obefazimod treatment provides continued improvement in clinical symptoms of disease, with a substantial proportion of patients in clinical remission, and an overall good safety profile. With a novel mechanism of action, obefazimod is an orally available small molecule with anti-inflammatory properties through the specific and selective upregulation of miR-124 expression. The aim of this paper is to critically review the available evidence related to pharmacokinetics and pharmacodynamics, and to discuss the potential clinical implications of this first-in-class oral small molecule.

Targeting Human Proteins for Antiviral Drug Discovery and Repurposing Efforts: A Focus on Protein Kinases.

Despite the great technological and medical advances in fighting viral diseases, new therapies for most of them are still lacking, and existing antivirals suffer from major limitations regarding drug resistance and a limited spectrum of activity. In fact, most approved antivirals are directly acting antiviral (DAA) drugs, which interfere with viral proteins and confer great selectivity towards their viral targets but suffer from resistance and limited spectrum. Nowadays, host-targeted antivirals (HTAs) are on the rise, in the drug discovery and development pipelines, in academia and in the pharmaceutical industry. These drugs target host proteins involved in the virus life cycle and are considered promising alternatives to DAAs due to their broader spectrum and lower potential for resistance. Herein, we discuss an important class of HTAs that modulate signal transduction pathways by targeting host kinases. Kinases are considered key enzymes that control virus-host interactions. We also provide a synopsis of the antiviral drug discovery and development pipeline detailing antiviral kinase targets, drug types, therapeutic classes for repurposed drugs, and top developing organizations. Furthermore, we detail the drug design and repurposing considerations, as well as the limitations and challenges, for kinase-targeted antivirals, including the choice of the binding sites, physicochemical properties, and drug combinations.

Protein Phosphatases: A Neglected Target Family for Drug Discovery

The gene family of protein phosphatases is a rich but under-exploited source of therapeutically validated drug targets modulating signal transduction pathways. Unlike the kinase family, research and development activities have not yet yielded any approved small-molecule drugs against a phosphatase. Approximately 20 years ago, the phosphatase family was classified as undruggable and intractable. This was primarily due to the spectacular failure of the cumulated industry-wide drug discovery efforts to develop PTP1B inhibitors. Recently, allosteric inhibitors against SHP2, a member of the phosphatase family, have entered clinical trails, which has reawakened industry’s interest towards this neglected enzyme family. This contribution reviews the recent R&amp;D trends around small-molecule efforts towards phosphatase modulators over the last years, rather than providing an exhaustive review of the field of allosteric phosphatase inhibitors.

Recent Advances and Mechanistic Insights into Antibacterial Activity, Antibiofilm Activity, and Cytotoxicity of Silver Nanoparticles.

The substantial increase in multidrug-resistant (MDR) pathogenic bacteria is a major threat to global health. Recently, the Centers for Disease Control and Prevention reported possibilities of greater deaths due to bacterial infections than cancer. Nanomaterials, especially small-sized (size ≤10 nm) silver nanoparticles (AgNPs), can be employed to combat these deadly bacterial diseases. However, high reactivity, instability, susceptibility to fast oxidation, and cytotoxicity remain crucial shortcomings for their uptake and clinical application. In this review, we discuss various AgNPs-based approaches to eradicate bacterial infections and provide comprehensive mechanistic insights and recent advances in antibacterial activity, antibiofilm activity, and cytotoxicity (both in vitro and in vivo) of AgNPs. The mechanistic of antimicrobial activity involves four steps: (i) adhesion of AgNPs to cell wall/membrane and its disruption; (ii) intracellular penetration and damage; (iii) oxidative stress; and (iv) modulation of signal transduction pathways. Numerous factors affecting the bactericidal activity of AgNPs such as shape, size, crystallinity, pH, and surface coating/charge have also been described in detail. The review also sheds light on antimicrobial photodynamic therapy and the role of AgNPs versus Ag+ ions release in bactericidal activities. In addition, different methods of synthesis of AgNPs have been discussed in brief.

HDL Composition, Heart Failure, and Its Comorbidities.

Although research on high-density lipoprotein (HDL) has historically focused on atherosclerotic coronary disease, there exists untapped potential of HDL biology for the treatment of heart failure. Anti-oxidant, anti-inflammatory, and endothelial protective properties of HDL could impact heart failure pathogenesis. HDL-associated proteins such as apolipoprotein A-I and M may have significant therapeutic effects on the myocardium, in part by modulating signal transduction pathways and sphingosine-1-phosphate biology. Furthermore, because heart failure is a complex syndrome characterized by multiple comorbidities, there are complex interactions between heart failure, its comorbidities, and lipoprotein homeostatic mechanisms. In this review, we will discuss the effects of heart failure and associated comorbidities on HDL, explore potential cardioprotective properties of HDL, and review novel HDL therapeutic targets in heart failure.

Essential Trace Metals as Countermeasure for Lead Toxicity.

Lead (Pb) is the most common toxic heavy metal that is physiologically non-essential and imposes health complications in animals and humans. Chelation therapy is considered as the definite therapy for acute lead toxicity; clinical uses of chelating agents are not recommended in long-term lead toxicity and in children. Research reveals that essential trace metals can counteract empirical Pb toxicity. This article collates the prototypical evidence of the preventive action of essential trace metals towards Pb toxicity in animals. Zinc, selenium, and their combinations are effective here. The key mechanisms of homeostasis of essential metals and cytoprotection are: modulation of signal transduction pathways of apoptosis, inflammation and immune functions (for selenium), attenuation of oxidative stress by augmenting non-enzymatic and enzymatic antioxidative systems and interference in lead accumulation in the body. By means of these mechanisms, these essential trace metals may counteract long-term lead toxicity for susceptible subjects. These mineral nutritional supplementation can easily be employed with no or less adverse effects compared to the typical chelation treatment.

Screening of selected ageing-related proteins that extend chronological life span in yeast Saccharomyces cerevisiae

Ageing-related proteins play various roles such as regulating cellular ageing, countering oxidative stress, and modulating signal transduction pathways amongst many others. Hundreds of ageing-related proteins have been identified, however the functions of most of these ageing-related proteins are not known. Here, we report the identification of proteins that extended yeast chronological life span (CLS) from a screen of ageing-related proteins. Three of the CLS-extending proteins, Ptc4, Zwf1, and Sme1, contributed to an overall higher survival percentage and shorter doubling time of yeast growth compared to the control. The CLS-extending proteins contributed to thermal and oxidative stress responses differently, suggesting different mechanisms of actions. The overexpression of Ptc4 or Zwf1 also promoted rapid cell proliferation during yeast growth, suggesting their involvement in cell division or growth pathways.

Nepetin Acts as a Multi-Targeting Inhibitor of Protein Tyrosine Phosphatases Relevant to Insulin Resistance.

Protein tyrosine phosphatases (PTPs) are essential modulators of signal transduction pathways and has been implicated in many human diseases such as cancer, diabetes, obesity, autoimmune disorders, and neurological diseases, indicating that PTPs are next-generation drug targets. Since PTPN1, PTPN2, and PTPN11 have been reported to be negative regulators of insulin action, the identification of PTP inhibitors may be an effective strategy to develop therapeutic agents for the treatment of type 2 diabetes. In this study, we observed for the first time that nepetin inhibits the catalytic activity of PTPN1, PTPN2, and PTPN11 in vitro, indicating that nepetin acts as a multi-targeting inhibitor of PTPN1, PTPN2, and PTPN11. Furthermore, treatment of mature 3T3-L1 adipocytes with 20 μM nepetin stimulates glucose uptake through AMPK activation. Taken together, our findings provide evidence that nepetin, a multi-targeting inhibitor of PTPN1, PTPN2, and PTPN11, could be a promising therapeutic candidate for the treatment of type 2 diabetes.

Therapeutic role of flavonoids and flavones in cancer prevention: Current trends and future perspectives

Cancer is one of notorious diseases across the globe.Therapeutic approaches for cancer are often expensive and develop severe side effects, and usually result comorbidities among the cancer survivors. Identifying novel therapies for treatment will reduce comorbidities in curing these diseases. It has been reported that flavones, a sub-class of flavonoid can act as a potent anticancer agent. Many experimental results displayed that flavones modulate signal transduction pathways in carcinogenesis. Flavones have been found to control cell cycle progression, oxidative stress, angiogenesis and metastasis alongwith some molecular pathways that ultimately prevent the progression of the diseases. Flavones have shown to possess a considerable as cancer preventive agents. As per the reports, flavones rich diet is beneficial, decreased risk of breast cancer, skin, digestive system, certain hematological malignancies and prostate cancer. Apart from cancer, flavones are also effective in improving other disease conditions such as cardiovascular and neurological diseases. Hence, these are the prime target in natural product and drug discovery research. Based on existing findings, it can concluded that more extensive research is needed to understand detailed beneficial properties of flavones along with biochemical mechanisms that drive these medicinal properties.

Methionine sulfoxide and the methionine sulfoxide reductase system as modulators of signal transduction pathways: a review.

Methionine oxidation and reduction is a common phenomenon occurring in biological systems under both physiological and oxidative-stress conditions. The levels of methionine sulfoxide (MetO) are dependent on the redox status in the cell or organ, and they are usually elevated under oxidative-stress conditions, aging, inflammation, and oxidative-stress related diseases. MetO modification of proteins may alter their function or cause the accumulation of toxic proteins in the cell/organ. Accordingly, the regulation of the level of MetO is mediated through the ubiquitous and evolutionary conserved methionine sulfoxide reductase (Msr) system and its associated redox molecules. Recent published research has provided new evidence for the involvement of free MetO or protein-bound MetO of specific proteins in several signal transduction pathways that are important for cellular function. In the current review, we will focus on the role of MetO in specific signal transduction pathways of various organisms, with relation to their physiological contexts, and discuss the contribution of the Msr system to the regulation of the observed MetO effect.

Ratiometric and reversible detection of endogenous SO2 and HCHO in living cells and mice by a near-infrared and dual-emission fluorescent probe

Abstract The small signal transmitters SO2 can elaborately modulate signal transduction pathways. Endogenous formaldehyde (FA) can toxify protein and DNA as a crosslinking agent besides functions in the aspect of spatial memory and cognitive ability. Both SO2 and FA are tightly associated with neurological disorders, cardiovascular diseases. Therefore, it is significant and challenging to monitor the real-time dynamic fluctuation of SO2 and FA in cells or animals. Toward this end, for the first time, a near-infrared (NIR) dual-emission fluorescent probe (BCou-BP) for SO2 and FA was developed based on the rational combination of benzypylium and benzo[g]coumarin cores through tuning the conjugation and rigidity of the fluorophore units. Thus, this rational design affords the new cationic probe the ratiometric detection ability (F604/F694) toward mitochondrial SO2 with a fast response time of 10 s, as well as toward FA in 170 s. Endogenous FA could restore the fluorescence at 694 nm of BCou-BP due to the capture of SO2 from decomposition of the adduct BCou-BP-SO3H. The powerful probe succeeded in real-time visualizing the dynamic change of endogenous mitochondrial SO2 and FA in living cells and mice.

A stress associated protein from Chinese wild Vitis amurensis, VaSAP15, enhances the cold tolerance of transgenic grapes

Stress associated protein (SAP) gene family can respond to a variety of biotic and abiotic stresses, and plays an important role in the process of improving the resistance of plants. In this study, we cloned a novel gene VaSAP15 from Chinese wild Vitis amurensis and validated its function in cold stress. Our data revealed that VaSAP15 protein localized in both nucleus and cell membrane. The SAP15 gene exhibited specific tissue expression in different grape genotypes, and strongly expressed in the roots of V. amurensis accession ‘Shuangyou’ (cold-tolerant) and in the stems of V. vinifera cultivar ‘Red Globe’ (cold-sensitive), respectively. Overexpressed VaSAP15 ‘Thompson Seedless’ (V. vinifera) lines were obtained by agrobacterium-mediated method. After cold stress at 0℃, the damage degree of transgenic line leaves was significantly lower than that of wild-type (WT), transgenic lines have the lower malondialdehyde (MDA) and electrolyte leakage (EL) and the higher activities of superoxide dismutase (SOD), peroxidase (POD) and catalase (CAT). Furthermore, the relative expression level of some cold-related genes including CBF1, CBF2, CBF3, COR27, RD29B and NCED1 were significantly up-regulated in transgenic lines. Besides, an interacting protein with VaSAP15, VaPDI1 (protein disulfide-isomerase), was screened out by yeast two-hybrid and verified by bimolecular fluorescence complementation assay. These results suggested that VaSAP15 may enhance grapevine cold tolerance through interacting with other proteins such as VaPDI1, which modulates signal transduction pathways and regulates the response of genes to environmental stresses in grapevine.