Intracellular Signaling Factors Research Articles

The therapeutic potential of microRNAs to ameliorate spinal cord injury by regulating oligodendrocyte progenitor cells and remyelination.

Spinal cord injury (SCI) can cause loss of sensory and motor function below the level of injury, posing a serious threat to human health and quality of life. One significant characteristic feature of pathological changes following injury in the nervous system is demyelination, which partially contributes to the long-term deficits in neural function after injury. The remyelination in the central nervous system (CNS) is mainly mediated by oligodendrocyte progenitor cells (OPCs). Numerous complex intracellular signaling and transcriptional factors regulate the differentiation process from OPCs to mature oligodendrocytes (OLs) and myelination. Studies have shown the importance of microRNA (miRNA) in regulating OPC functions. In this review, we focus on the demyelination and remyelination after SCI, and summarize the progress of miRNAs on OPC functions and remyelination, which might provide a potential therapeutic target for SCI treatments.

Recent Research on Mechanisms of Feeding Regulation in Chicks.

Food intake affects poultry productivity. A complete understanding of these regulatory mechanisms provides new strategies to improve productivity. Food intake is regulated by complex mechanisms involving many factors, including the central nervous system, gastrointestinal tract, hormones, and nutrients. Although several studies have been conducted to elucidate regulatory mechanisms in chickens, the mechanisms remain unclear. To update the current knowledge on feeding regulation in chickens, this review focuses on recent findings that have not been summarized in previous reviews, including spexins, adipokines, neurosecretory proteins GL and GM, and central intracellular signaling factors.

Transcriptomics reveals key regulatory pathways and genes associated with skin diseases induced by face paint usage

The use of face paint cosmetics can cause skin diseases in opera performers due to the presence of heavy metals and other toxic ingredients in the cosmetics. However, the underlying molecular mechanism for these diseases remains unknown. Here we examined the transcriptome gene profile of human skin keratinocytes exposed to artificial sweat extracts of face paints, and identified the key regulatory pathways and genes, using RNA sequencing technique. Bioinformatics analyses suggested that the face paint exposure induced the differentially expression of 1531 genes and enriched inflammation-relevant TNF and IL-17 signaling pathways after just 4 h of exposure. Inflammation-relevant genes CREB3L3, FOS, FOSB, JUN, TNF, and NFKBIA were identified as the potential regulatory genes, and SOCS3 capable to prevent inflammation-induced carcinogenesis as the hub-bottleneck gene. Long-term exposure (24 h) could exacerbate inflammation, accompanied by interference in cellular metabolism pathways, and the potential regulatory genes (ATP1A1, ATP1B1, ATP1B2, FXYD2, IL6, and TNF) and hub-bottleneck genes (JUNB and TNFAIP3) were all related to inflammation induction and other adverse responses. We proposed that the exposure to face paint might cause the inflammatory factors TNF and IL-17, which are encoded by the genes TNF and IL17, to bind to receptors and activate TNF and IL-17 signaling pathways, leading to the expression of cell proliferation factors (CREB and AP-1) and proinflammatory mediators including transcription factors (FOS, JUN, and JUNB), inflammatory factors (TNF-α and IL6), and intracellular signaling factors (TNFAIP3). This finally resulted in cell inflammation, apoptosis, and other skin diseases. TNF was identified as the key regulator and connector in all the enriched signaling pathways. Our study provides the first insights into the cytotoxicity mechanism of face paints to skin cells and highlights the need for stricter regulations in face paint safety.

Identification of a novel gene signature for neuroblastoma differentiation using a Boolean implication network.

Although induction of differentiation represents an effective strategy for neuroblastoma treatment, the mechanisms underlying neuroblastoma differentiation are poorly understood. We generated a computational model of neuroblastoma differentiation consisting of interconnected gene clusters identified based on symmetric and asymmetric gene expression relationships. We identified a differentiation signature consisting of series of gene clusters comprised of 1251 independent genes that predicted neuroblastoma differentiation in independent datasets and in neuroblastoma cell lines treated with agents known to induce differentiation. This differentiation signature was associated with patient outcomes in multiple independent patient cohorts and validated the role of MYCN expression as a marker of neuroblastoma differentiation. Our results further identified novel genes associated with MYCN via asymmetric Boolean implication relationships that would not have been identified using symmetric computational approaches and that were associated with both neuroblastoma differentiation and patient outcomes. Our differentiation signature included a cluster of genes involved in intracellular signaling and growth factor receptor trafficking pathways that is strongly associated with neuroblastoma differentiation, and we validated the associations of UBE4B, a gene within this cluster, with neuroblastoma cell and tumor differentiation. Our findings demonstrate that Boolean network analyses of symmetric and asymmetric gene expression relationships can identify novel genes and pathways relevant for neuroblastoma tumor differentiation that could represent potential therapeutic targets.

Enhanced Anti-Cancer Effects of Conditioned Medium from Hypoxic Human Adult Dermal Fibroblasts on Cervical Cancer Cells.

Hypoxia regulates fibroblast function by changing intracellular signaling and secretion factors, that influence the states of nearby cells. In this work, we investigated how medium (CM) from human adult dermal fibroblasts (HDFs) cultured in normoxic and hypoxic conditions affected cervical cancer (HeLa) cells. The HeLa cells showed decreased cell viability, increased apoptosis, and cell cycle arrest in response to CM from hypoxic-cultured HDFs (H-CM) compared with CM from normoxic-cultured HDFs (N-CM). Among the proteins up-regulated (>2-fold) in H-CM compared with N-CM, lymphotoxin-beta receptor (LTBR) decreased the viability of HeLa cells. Among the intracellular proteins down-regulated (>2-fold) in HeLa cells treated with H-CM compared with N-CM, the most enriched biological process GO term and KEGG pathway were protein deubiquitination and hsa05166:HTLV-I infection, respectively. In the protein–protein interaction network of intracellular proteins with altered expression (>2-fold), 1 up-regulated (TNF) and 8 down-regulated (ESR1, MCL1, TBP, CD19, LCK, PCNA, CHEK1, and POLA1) hub proteins were defined. Among the down-regulated hub proteins, the most enriched biological process GO term and KEGG pathway were leading strand elongation and hsa05166:HTLV-I infection, respectively. This study reveals that H-CM had stronger anti-cancer effects on cervical cancer cells than N-CM and induced intracellular signaling patterns related to those enhanced anti-cancer effects.

Genetic Background of Polycythemia Vera.

Polycythemia vera belongs to myeloproliferative neoplasms, essentially by affecting the erythroblastic lineage. JAK2 alterations have emerged as major driver mutations triggering PV-phenotype with the V617F mutation detected in nearly 98% of cases. That’s why JAK2 targeting therapeutic strategies have rapidly emerged to counter the aggravation of the disease. Over decades of research, to go further in the understanding of the disease and its evolution, a wide panel of genetic alterations affecting multiple genes has been highlighted. These are mainly involved in alternative splicing, epigenetic, miRNA regulation, intracellular signaling, and transcription factors expression. If JAK2 mutation, irrespective of the nature of the alteration, is known to be a crucial event for the disease to initiate, additional mutations seem to be markers of progression and poor prognosis. These discoveries have helped to characterize the complex genomic landscape of PV, resulting in potentially new adapted therapeutic strategies for patients concerning all the genetic interferences.

Molecular Mechanisms of Functional Adrenocortical Adenoma and Carcinoma: Genetic Characterization and Intracellular Signaling Pathway.

The adrenal cortex produces steroid hormones as adrenocortical hormones in the body, secreting mineralocorticoids, glucocorticoids, and adrenal androgens, which are all considered essential for life. Adrenocortical tumors harbor divergent hormonal activity, frequently with steroid excess, and disrupt homeostasis of the body. Aldosterone-producing adenomas (APAs) cause primary aldosteronism (PA), and cortisol-producing adenomas (CPAs) are the primary cause of Cushing’s syndrome. In addition, adrenocortical carcinoma (ACC) is a highly malignant cancer harboring poor prognosis. Various genetic abnormalities have been reported, which are associated with possible pathogenesis by the alteration of intracellular signaling and activation of transcription factors. In particular, somatic mutations in APAs have been detected in genes encoding membrane proteins, especially ion channels, resulting in hypersecretion of aldosterone due to activation of intracellular calcium signaling. In addition, somatic mutations have been detected in those encoding cAMP-PKA signaling-related factors, resulting in hypersecretion of cortisol due to its driven status in CPAs. In ACC, mutations in tumor suppressor genes and Wnt-β-catenin signaling-related factors have been implicated in its pathogenesis. In this article, we review recent findings on the genetic characteristics and regulation of intracellular signaling and transcription factors in individual tumors.

Regulation of Parkin-dependent mitophagy by Bcl-2-associated athanogene (BAG) family members.

Regulation of Parkin-dependent mitophagy by Bcl-2-associated athanogene (BAG) family members.

Effects of biogenic amines on the immune response and immunoregulation mechanism in hemocytes of Litopenaeus vannamei in vitro

The effects of three biogenic amines (DA, NE and 5-HT) on the immune signaling pathway and immune response of hemocytes in shrimp were investigated through in vitro experiments. The results showed that the G protein effectors (AC, PLC), the second messengers (cAMP, DAG), Calmodulin (CaM) and protein kinases (PKA, PKC) of DA and NE groups shared a similar trend in which all intracellular signaling factors increased significantly and reached the maximum at 3 h. The concentrations of AC, cAMP and PKA in 5-HT groups decreased significantly compared with the control group, while the concentrations of PLC, CaM, DAG and PKC in 5-HT groups increased markedly. The immune parameters such as total hemocyte count (THC), cell viability, antibacterial activity and bacteriolytic activity, as well as prophenoloxidase (proPO) activity in three biogenic amines groups decreased significantly, while the phenoloxidase (PO) activity increased significantly. The phagocytic activity in DA and NE groups decreased significantly, while that in 5-HT groups increased markedly and reached the highest level at 1 h. Among these three biogenic amines, DA showed the strongest effect on the immune activity of the hemocytes, whereas 5-HT had the least effect. In addition, we speculated that DA and NE might regulate phagocytosis by activating intracellular AC-cAMP-PKA pathway while 5-HT might inhibit intracellular AC-cAMP-PKA pathway. Moreover, the activation of proPO system might be related to PLC-DAG-PKC and PLC-CaM pathway.

MicroRNA-532-3p Regulates Pro-Inflammatory Human THP-1 Macrophages by Targeting ASK1/p38 MAPK Pathway.

Inflammation is a complex biological process which alters the normal physiological function of the immune system resulting in an abnormal microenvironment that leads to several clinical complications. The process of inflammation is mediated through various intracellular signaling factors inside the cells. Apoptosis signal-regulating kinase 1 (ASK1) is an inflammation-derived kinase that controls the activation of other family of kinases such as p38 mitogen-activated protein kinases (p38 MAPKs), which mediates various the inflammatory processes. In this study, we cultured THP-1 macrophage cells to undergo inflammatory proliferation with LPS (1μg/ml) and TNFα (10ng/ml) stimulation. Initial in silico analysis was utilized to predict novel microRNAs (miRNAs) that target ASK1 signaling and its expression levels in LPS and TNFαstimulated THP-1 cells were estimated. Among the miRNAs, miR-532-3p showcased the highest binding affinity towards ASK1 kinase. We witnessed that transient transfection of miR-532-3p diminished the levels of ASK1 and downstream phosphorylation/translocation of p38 MAPK. Furthermore, direct targeting of ASK1 resulted in regulation of uncontrolled release of cytokines (TNFα, IL-6, and IL-23) and chemokines (GM-CSF and MIP-2α). Overall, we suggest that miR-532-3p attenuates the pro-inflammatory nature of macrophages by targeting ASK1/p38 MAPK signaling pathway and can be used as a molecular intervention for treating inflammatory diseases.

Recent advances of GOLM1 in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the most common liver malignancies and is a leading cause of cancer-related deaths. Most HCC patients are diagnosed at an advanced stage and current treatments show poor therapeutic efficacy. It is particularly urgent to explore early diagnosis methods and effective treatments of HCC. There are a growing number of studies that show GOLM1 is one of the most promising markers for early diagnosis and prognosis of HCC. It is also involved in immune regulation, activation and degradation of intracellular signaling factors and promotion of epithelial–mesenchymal transition. GOLM1 can promote HCC progression and metastasis. The understanding of the GOLM1 regulation mechanism may provide new ideas for the diagnosis, monitoring and treatment of HCC.

Progress in the development of antiplatelet agents: Focus on the targeted molecular pathway from bench to clinic.

Antiplatelet drugs serve as a first-line antithrombotic therapy for the management of acute ischemic events and the prevention of secondary complications in vascular diseases. Numerous antiplatelet therapies have been developed; however, currently available agents are still associated with inadequate efficacy, risk of bleeding, and variability in individual response. Understanding the mechanisms of platelet involvement in thrombosis and the clinical development process of antiplatelet agents is critical for the discovery of novel agents. The functions of platelets in thrombosis are regulated by two major mechanisms: the interaction between surface receptors and their ligands, and the downstream intracellular signaling pathways. Recently, most of the progress made in antiplatelet drug development has been achieved with P2Y receptor antagonists. Additionally, the usage of GP IIb/IIIa receptor antagonists has decreased, because it is associated with a higher risk of bleeding and thrombocytopenia. Agents targeting other platelet surface receptors such as PARs, TP receptor, EP3 receptor, GPIb-IX-V receptor, P-selectin, as well as intracellular signaling factors, such as PI3Kβ, have been evaluated in an attempt to develop the next generation of antiplatelet drugs, reduce or eliminate interpatient variability of drug efficacy and significantly lower the risk of drug-induced bleeding. The aim of this review is to describe the pathways of platelet activation in thrombosis, and summarize the development process of antiplatelet agents, as well as the preclinical and clinical evaluations performed on these agents.

Transcriptomic profile of anterior pituitary cells of pigs is affected by adiponectin

Adiponectin is thought to be involved in the regulation of metabolic homeostasis and reproductive processes. It also has an important role in the modulation of female reproductive functions, both directly and by affecting the secretory functions of the hypothalamic-pituitary-gonadal axis. The main aim of this study was to determine the effect of adiponectin on global gene expression and on differentially expressed genes (DE-genes) regulated by adiponectin in anterior pituitary (AP) cells of pigs. The changes in the transcriptomic profile of AP cells of pigs were examined using the Porcine (V2) two-colour gene expression microarray, 4 × 44. An analysis of data from the microarray experiment indicated there were 716 DE-genes. A total of 466 genes (220 up-regulated and 246 down-regulated) with fold change greater than 1.2 (P < 0.05) were subsequently selected for further analysis. Gene ontology was analysed based on a list of DE-genes. A list of biological processes was generated for both up-regulated and down-regulated DE-genes. The products of up-regulated DE-genes were involved in 60 biological processes, whereas for down-regulated products there were 18 processes. An analysis of the interactions between DE-genes indicated that adiponectin interacted with genes that potentially encode intracellular signalling pathways and factors which regulate reproductive functions. Furthermore, nine genes were selected from the list of DE-genes to confirm microarray results by quantitative PCR. The results enhance the knowledge about adiponectin's role in the pituitary functions of pigs and provide valuable insights for further studies into adiponectin's mechanism of action in the pituitary.

Evidence that dopamine is involved in neuroendocrine regulation, gill intracellular signaling pathways and ion regulation in Litopenaeus vannamei.

The transport of ions and ammonia in gills may be regulated by neuroendocrine factors. In order to explore the mechanism of dopamine (DA) regulation, we investigated hemolymph neuroendocrine hormones, gill intracellular signaling pathways, ion and ammonia transporters, hemolymph osmolality and ammonia concentration in Litopenaeus vannamei after injection of 10-7 and 10-6mol DA per shrimp. The data showed a significant increase in crustacean hyperglycemic hormone (CHH) concentration at 1-12 h and a transient significant decrease in corticotrophin-releasing hormone (CRH), adrenocorticotropic hormone (ACTH) and cortisol concentration under DA stimulation. The up-regulation of guanylyl cyclase (GC) mRNA, cyclic guanosine monophosphate (cGMP) and protein kinase G (PKG) concentration, together with the down-regulation of DA receptor D4 mRNA and up-regulation of cyclic adenosine monophosphate (cAMP), protein kinase A (PKA), diacylglycerol (DAG) and protein kinase C (PKC) concentration suggested the activation of complicated intracellular signaling pathways. The expression of cAMP response element-binding protein (CREB), FXYD2 and 14-3-3 protein mRNA was significantly increased by PKA regulation. The increase in Na+/K+-ATPase (NKA) activity and the stabilization of V-type H+-ATPase (V-rATPase) activity were accompanied by an up-regulation of K+ channel, Na+/K+/2Cl- cotransporter (NKCC), Rh protein and vesicle associated membrane protein (VAMP) mRNA, resulting in an increase in hemolymph osmolality and a decrease in hemolymph ammonia concentration. These results suggest that DA stimulates the secretion of CHH and inhibits the release of cortisol, which activates intracellular signaling factors to facilitate ion and ammonia transport across the gills, and may not affect intracellular acidification.

In vitro effect of orexin A on the transcriptomic profile of the endometrium during early pregnancy in pigs

Orexin A belongs to the group of hypothalamic-derived peptides that are involved in a number of processes, such as regulation of energy metabolism, control of food intake and regulation of the reproductive system, by influencing the hypothalamic-pituitary-ovarian axis. Orexin A is also present in the endometrium, myometrium and placenta, which indicates that it may function as an important local regulator of the reproductive functions. The aim of this study was to explore the effects of orexin A on global gene expression in the endometrium of pigs during early gestation, on days 15 to 16 of pregnancy (implantation period). Orexin A altered the expression of 1,242 genes. In this group, 1,104 genes had a fold change greater than 1.2 (P < 0.05). In the group of genes with a fold change that was greater than 1.2, the expression of 457 genes were increased and 647 decreased because of the effects of orexin A. An analysis of the interactions between differentially expressed genes demonstrated that orexin A interacts with genes that potentially encode intracellular signalling pathways and factors regulating reproductive functions in the endometrium. The data from the present study indicate that orexin A affects a number of genes and processes in the endometrium of pregnant pigs and may be regarded as an important regulator of implantation, depending on maternal nutritional status.

Cardioprotective signalling: Past, present and future

A few decades ago, cardiac muscle was discovered to possess signalling pathways that, when activated, protect the myocardium against the damage induced by ischaemia-reperfusion. The ability of cardiac muscle to protect itself against injury has been termed ‘cardioprotection’. Many compounds and procedures can trigger cardioprotection including conditionings (exposure to brief episodes of ischaemia-reperfusion to protect against sustained ischaemia-reperfusion), hypoxia, adenosine, acetylcholine, adrenomedullin, angiotensin, bradykinin, catecholamines, endothelin, estrogens, phenylephrine, opioids, testosterone, and many more. These triggers activate many intracellular signalling factors including protein kinases, different enzymes, transcription factors and defined signalling pathways to target structures in mitochondria, sarcoplasmic reticulum, nucleus and sarcolemma to mediate cardioprotection. Although a lot of information about cardioprotection has been acquired, there are still two major outstanding issues to be addressed in the future 1) better understanding of spatio-temporal relationships between signalling elements, and; 2) devising therapeutic strategies against myocardial diseases based on cardioprotective signalling. Further research is required to paint integral picture of cardioprotective signalling and more clinical studies are required to properly test clinical efficacy and safety of potential cardioprotective strategies. Therapies against cardiac diseases based on cardioprotective strategies would be a perfect adjunct to current therapeutic strategies based on restitution of coronary blood flow and regulation of myocardial metabolic demands.

Combination of l-cystein and reduced glutathione in tris-citric acid based extender improves the post thaw quality of dromedary camel spermatozoa

Orexin A belongs to the group of hypothalamic-derived peptides that are involved in a number of processes, such as regulation of energy metabolism, control of food intake and regulation of the reproductive system, by influencing the hypothalamic-pituitary-ovarian axis. Orexin A is also present in the endometrium, myometrium and placenta, which indicates that it may function as an important local regulator of the reproductive functions. The aim of this study was to explore the effects of orexin A on global gene expression in the endometrium of pigs during early gestation, on days 15 to 16 of pregnancy (implantation period). Orexin A altered the expression of 1,242 genes. In this group, 1,104 genes had a fold change greater than 1.2 (P < 0.05). In the group of genes with a fold change that was greater than 1.2, the expression of 457 genes were increased and 647 decreased because of the effects of orexin A. An analysis of the interactions between differentially expressed genes demonstrated that orexin A interacts with genes that potentially encode intracellular signalling pathways and factors regulating reproductive functions in the endometrium. The data from the present study indicate that orexin A affects a number of genes and processes in the endometrium of pregnant pigs and may be regarded as an important regulator of implantation, depending on maternal nutritional status.

Measuring zinc in biological nanovesicles by multiple analytical approaches

Exosomes are nanovesicles known to mediate intercellular communication. Although it is established that zinc ions can act as intracellular signaling factors, the measurement of zinc in circulating nanovesicles has not yet been attempted. Providing evidence of the existence of this zinc fraction and methods for its measurement might be important to advance our knowledge of zinc status and its relevance in diseases.Exosomes from 0.5 ml of either fresh or frozen human plasma were isolated by differential centrifugation. A morphological and dimensional evaluation at the nanoscale level was performed by atomic force microscopy (AFM) and Transmission Electron Microscopy (TEM).Energy Dispersive X-Ray Microanalysis (EDX) revealed the elemental composition of exosomes and their respective total Zinc content on a quantitative basis. The zinc mole fraction (in at%) was correlated to the phosphorous mole fraction, which is indicative for exosomal membrane material. Both fresh (Zn/P 0.09 ± 0.01) and frozen exosomes (Zn/P 0.08 ± 0.02) had a significant zinc content, which increased up to 1.09 ± 0.12 for frozen exosomes when treated with increasing amounts of zinc (100–500 μM; each p < 0.05). Interestingly, after zinc addition, the Calcium mole fractions decreased accordingly suggesting a possible exchange by zinc.In order to estimate the intra-exosomal labile zinc content, an Imaging Flow Cytometry approach was developed by using the specific membrane permeable zinc-probe Fluozin-3AM. A labile zinc content of 0.59 ± 0.27 nM was calculated but it is likely that the measurement may be affected by purification and isolation conditions. This study suggests that circulating nano-vesicular-zinc can represent a newly discovered zinc fraction in the blood plasma whose functional and biological properties will have to be further investigated in future studies.

ADCC responses and blocking of EGFR-mediated signaling and cell growth by combining the anti-EGFR antibodies imgatuzumab and cetuximab in NSCLC cells.

Imgatuzumab is a novel glycoengineered anti-epidermal growth factor receptor (EGFR) monoclonal antibody optimized to induce both antibody-dependent cellular cytotoxicity (ADCC) and EGFR signal transduction inhibition. We investigated anti-EGFR monoclonal antibodies imgatuzumab and cetuximab–induced internalization and membranous turnover of EGFR, and whether this affected imgatuzumab–mediated ADCC responses and growth inhibition of non-small cell lung cancer (NSCLC) cells.In a panel of wild-type EGFR expressing human NSCLC cell lines, membranous and total EGFR levels were downregulated more effectively by imgatuzumab when compared with cetuximab. Imgatuzumab plus cetuximab enhanced EGFR internalization and reduced membranous turnover of EGFR, resulting in an even stronger downregulation of EGFR. Immunofluorescent analysis showed that combined treatment increased clustering of receptor-antibody complexes and directed internalized EGFR to lysosomes. The antibody combination potently inhibited intracellular signaling and epidermal growth factor (EGF)-dependent cell proliferation. More importantly, robust EGFR downregulation after 72 hours with the antibody combination did not impair ADCC responses.In conclusion, imgatuzumab plus cetuximab leads to a strong downregulation of EGFR and superior cell growth inhibition in vitro without affecting antibody-induced ADCC responses. These findings support further clinical exploration of the antibody combination in EGFR wild-type NSCLC.

Over-Expression of Activin-βC Is Associated with Murine and Human Prostate Disease.

Activins are members of the TGF-β superfamily and have been linked to prostate cancer. There are four mammalian activin subunits (βA, βB, βC, and βE) that dimerize to form functional proteins. The role of activin-A (βA-βA) has been relatively well characterized and has been shown to generally inhibit growth in the prostate. In contrast, little is known about the biological function of the βC and βE subunits. Previous work indicated activin-C (βC-βC) to be an antagonist of activin-A. This is important because resistance to activin-A growth inhibition occurs during prostate cancer progression. This paradox is not currently well understood. Hence, we hypothesize that local expression of the activin-βC subunit antagonizes activin-A-dependent growth inhibition and represents a key factor contributing to acquired insensitivity to activin-A observed in prostate cancer progression. To test our hypothesis, we characterized the ventral prostate lobes of 9-month-old transgenic mice over-expressing activin-βC and examined the expression of activin-βA, activin-βC, and the activin intracellular signaling factor, Smad-2, in human prostate diseases. Prostate epithelial cell hyperplasia, low-grade prostatic intraepithelial neoplasia (PIN) lesions, alterations in cell proliferation, and reduced Smad-2 nuclear localization were evident in mice over-expressing activin-βC. Increased activin-βA and -βC subunit immunoreactive scores and decreased Smad-2 nuclear localization were also evident in human prostate cancer. This study suggests that over-expression of activin-βC is associated with murine and human prostate pathologies. We conclude that the activin-βC subunit may have therapeutic and/or diagnostic implications in human prostate disease.