Oncogene database

10451

VAV3

vav 3 guanine nucleotide exchange factor;VAV3;vav 3 guanine nucleotide exchange factor

VAV-3|guanine nucleotide exchange factor VAV3|vav 3 oncogene

1p13.3

protein-coding

The purpose of this research was to investigate the role of Vav3 oncogene in human prostate cancer. We found that expression of Vav3 was significantly elevated in androgen-independent LNCaP-AI cells in comparison with that in their androgen-dependent counterparts, LNCaP cells. Vav3 expression was also detected in other human prostate cancer cell lines (PC-3, DU145, and 22Rv1) and, by immunohistochemistry analysis, was detected in 32% (26 of 82) of surgical specimens of human prostate cancer. Knockdown expression of Vav3 by small interfering RNA inhibited growth of both androgen-dependent LNCaP and androgen-independent LNCaP-AI cells. In contrast, overexpression of Vav3 promoted androgen-independent growth of LNCaP cells induced by epidermal growth factor. Overexpression of Vav3 enhanced androgen receptor (AR) activity regardless of the presence or absence of androgen and stimulated the promoters of AR target genes. These effects of Vav3 could be attenuated by either phosphatidylinositol 3-kinase (PI3K) inhibitors or dominant-negative Akt and were enhanced by cotransfection of PI3K. Moreover, phosphorylation of Akt was elevated in LNCaP cells overexpressing Vav3, which could be blocked by PI3K inhibitors. Finally, we ascertained that the DH domain of Vav3 was responsible for activation of AR. Taken together, our data show that overexpression of Vav3, through the PI3K-Akt pathway, inappropriately activates AR signaling axis and stimulates cell growth in prostate cancer cells. These findings suggest that Vav3 overexpression may be involved in prostate cancer development and progression.

Although much is known about environmental factors that predispose individuals to hypertension and cardiovascular disease, little information is available regarding the genetic and signaling events involved. Indeed, few genes associated with the progression of these pathologies have been discovered despite intensive research in animal models and human populations. Here we identify Vav3, a GDP-GTP exchange factor that stimulates Rho and Rac GTPases, as an essential factor regulating the homeostasis of the cardiovascular system. Vav3-deficient mice exhibited tachycardia, systemic arterial hypertension and extensive cardiovascular remodeling. These mice also showed hyperactivity of sympathetic neurons from the time of birth. The high catecholamine levels associated with this condition led to the activation of the renin-angiotensin system, increased levels of kidney-related hormones and the progressive loss of cardiovascular and renal homeostasis. Pharmacological studies with drugs targeting sympathetic and renin-angiotensin responses confirmed the causative role and hierarchy of these events in the development of the Vav3-null mouse phenotype. These observations uncover the crucial role of Vav3 in the regulation of the sympathetic nervous system (SNS) and cardiovascular physiology, and reveal a signaling pathway that could be involved in the pathophysiology of human disease states involving tachycardia and sympathetic hyperactivity with unknown etiologies.

BACKGROUND: Our previous study revealed that Vav3 oncogene is overexpressed in human prostate cancer, activates androgen receptor, and stimulates growth in prostate cancer cells. The current study is to determine a potential role of Vav3 oncogene in human breast cancer and impact on estrogen receptor a (ERalpha)-mediated signaling axis. METHODS: Immunohistochemistry analysis was performed in 43 breast cancer specimens and western blot analysis was used for human breast cancer cell lines to determine the expression level of Vav3 protein. The impact of Vav3 on breast cancer cell growth was determined by siRNA knockdown of Vav3 expression. The role of Vav3 in ERalpha activation was examined in luciferase reporter assays. Deletion mutation analysis of Vav3 protein was performed to localize the functional domain involved in ERalpha activation. Finally, the interaction of Vav3 and ERalpha was assessed by GST pull-down analysis. RESULTS: We found that Vav3 was overexpressed in 81% of human breast cancer specimens, particularly in poorly differentiated lesions. Vav3 activated ERalpha partially via PI3K-Akt signaling and stimulated growth of breast cancer cells. Vav3 also potentiated EGF activity for cell growth and ERalpha activation in breast cancer cells. More interestingly, we found that Vav3 complexed with ERalpha. Consistent with its function for AR, the DH domain of Vav3 was essential for ERalpha activation. CONCLUSION: Vav3 oncogene is overexpressed in human breast cancer. Vav3 complexes with ERalpha and enhances ERalpha activity. These findings suggest that Vav3 overexpression may aberrantly enhance ERalpha-mediated signaling axis and play a role in breast cancer development and/or progression.

Our previous study revealed that Vav3 oncogene is overexpressed in human prostate cancer, activates androgen receptor (AR), and stimulates growth in prostate cancer cells. The purpose of this study is to further determine the potential role of Vav3 in prostate cancer development in genetically engineered mouse model. We generated Vav3 transgenic mice by targeted overexpression of a constitutive active Vav3 in the prostatic epithelium. We found that overexpression of Vav3 led to development of mouse prostatic intraepithelial neoplasia and prostate cancer at the age of as early as 3 months. The AR signaling axis and phosphatidylinositol 3-kinase-Akt signaling were elevated in the prostate glands of Vav3 transgenic mice. In addition to prostate cancer, Vav3 transgenic mice developed significant nonbacterial chronic prostatitis in the prostate gland with notable infiltration of lymphomononuclear cells (monocytes, lymphocytes, and plasma cells), which was associated with elevated incidence of prostate cancer. DNA microarray and signaling pathway analysis revealed that the top diseases and disorders were inflammatory diseases and cancer of the prostate gland in Vav3 transgenic mice. In vitro analysis showed that overexpression of Vav3 in prostate cancer cells enhanced nuclear factor-kappaB (NF-kappaB) activity, implicating an underlying mechanism of innate inflammatory response induced by elevated Vav3 activity. These data showed that Vav3 overexpression in the prostate epithelium enhanced both the AR signaling axis and NF-kappaB-mediated pathway, which potentially contributed to the development of nonbacterial prostatitis and prostate cancer.

Our previous studies revealed that Vav3 oncogene is overexpressed in human prostate cancer, enhances androgen receptor (AR)-mediated signaling, and may play a role in prostate cancer development and progression. The purpose of this study was to determine the molecular mechanisms responsible for AR activation by Vav3. We found that interaction between N-terminus and C-terminus of AR is essential for its elevated activity stimulated by Vav3. The DH and PH domains of Vav3 are involved in direct interaction with AR. Both cytoplasmic and nuclear levels of AR and Vav3 are elevated and their nuclear localization is further stimulated by DHT in androgen-independent LNCaP-AI cells relative to their parental androgen-dependent LNCaP cells. Vav3 is colocalized with AR, phospho(P)-Akt, and HER2 with a short term stimulation by EGF and DHT. PI3K inhibitor LY294002 blocks colocalization of Vav3 with P-Akt. Consistently, EGF and DHT stimulate Vav3 and AR interaction and enhance PI3K-Akt signaling. mutation of tyrosines to phenylalanines in the acidic domain or deletion of the SH2 and SH3 domains significantly enhances Vav3 ability for AR activation, while deletion of the DH domain abolishes this activity. Given that an elevated interaction of Vav3 with AR, P-Akt, and HER2 in both cytoplasm and nucleus upon the short-term of DHT stimulation, our data suggest that Vav3 may enhance non-genomic AR activity via PI3K-Akt signaling in addition to AR transcriptional activity and further support a role in androgen-independent growth in prostate cancer.

The dioxin receptor (AhR) is possibly the best characterized xenobiotic receptor because of its essential role in mediating the harmful effects of highly toxic environmental pollutants. Despite the fact that AhR-dependent toxicity is a major environmental concern, compelling evidence has recently been produced unveiling novel and remarkable endogenous functions of AhR in cell physiology and tissue homeostasis. Adding to its role in cell proliferation and differentiation, AhR is also involved in the control of cell adhesion and migration, both highly relevant tasks in development and in disease states such as cancer. Interestingly, the effect of AhR on cell migration is cell-type specific because it can sustain or slow down cell motility. Here, I will comment on our recent report showing that AhR is a positive regulator of fibroblast cells migration. Besides characterizing the phenotype of such mesenchymal cells, the most important single finding of our study is that AhR uses the cytoskeleton regulator and oncogen Vav3 to signal through small Rho GTPases, ultimately leading to the physiological control of cell adhesion and migration. These data reveal that AhR activity is required to maintain signaling pathways governing normal cell function and open the question of whether AhR plays a role in cell migration during development and in pathological conditions such as tumor metastasis.

Aryl hydrocarbon receptor (Ahr) is a transcriptional factor involved in detoxification responses to pollutants and in intrinsic biological processes of multicellular organisms. We recently described that Vav3, an activator of Rho/Rac GTPases, is an Ahr transcriptional target in embryonic fibroblasts. These results prompted us to compare the Ahr(-/-) and Vav3(-/-) mouse phenotypes to investigate the implications of this functional interaction in vivo. Here, we show that Ahr is important for Vav3 expression in kidney, lung, heart, liver, and brainstem regions. This process is not affected by the administration of potent Ahr ligands such as benzo[a]pyrene. We also report that Ahr- and Vav3-deficient mice display hypertension, tachypnea, and sympathoexcitation. The Ahr gene deficiency also induces the GABAergic transmission defects present in the Vav3(-/-) ventrolateral medulla, a main cardiorespiratory brainstem center. However, Ahr(-/-) mice, unlike Vav3-deficient animals, display additional defects in fertility, perinatal growth, liver size and function, closure, spleen size, and peripheral lymphocytes. These results demonstrate that Vav3 is a bona fide Ahr target that is in charge of a limited subset of the developmental and physiological functions controlled by this transcriptional factor. Our data also reveal the presence of sympathoexcitation and new cardiorespiratory defects in Ahr(-/-) mice.

Our previous study revealed that Vav3 oncogene and secretory phospholipase A2-IIa (sPLA2-IIa) are overexpressed in androgen-independent prostate cancer cells relative to their androgen-dependent counterparts and contribute to development of hormone refractory prostate cancer. Vav3 is a multiple function protein with both signaling molecule and coactivator activities. sPLA2-IIa is a downstream effector of HER/HER2-PI3K-Akt-NF-kappaB signaling and involved in inflammatory response and tumorigenesis. The aim of the current study was to determine whether Vav3 is involved in up-regulation of sPLA2-IIa expression, given that Vav3 signals in the HER/HER2-elicited pathway. Among 46 prostate cancer specimens examined, Vav3 and sPLA2-IIa are overexpressed in 48 and 83% human prostate cancers, respectively. Vav3 overexpression is significantly associated with a high level expression of sPLA2-IIa. In addition, significant Vav3 nuclear localization is observed in two prostate cancer specimens, supporting a coactivator activity in prostate cancer cells. Further analysis revealed that Vav3 up-regulates expression of the sPLA2-IIa gene at the transcriptional level via HER/HER2-PI3K-Akt-NF-kappaB signaling. These data revealed that Vav3 overexpression as an additional underlying mechanism contributes to elevated sPLA2-IIa expression in prostate cancer.

OBJECTIVES: We had previously reported that chronic hypoxia induces androgen-independent growth in the human prostate cancer cell line LNCaP. In this study, we have identified a key molecule, the Vav3 oncogene, and investigated the effects of Vav3 overexpression on cancer cell growth and malignant behavior and the possible apoptosis-inducing effect of Vav3 expression knockdown by small interfering ribonucleic acid (siRNA) in LNCaP cells under chronic hypoxia (LNCaP/CH). METHODS AND MATERIALS: Hypoxia-inducible oncogenes were identified by complementary deoxyribonucleic acid (cDNA) microarray and Ingenuity pathway Analysis in order to investigate gene ontology and functional pathways and networks. siRNA was used to knockdown the Vav3 target gene and analyze the effects on proliferation, invasion, migration, and apoptosis of LNCaP/CH cells. Vav3 cDNA was transfected into LNCaP cells under normoxia (LNCaP/N) to establish Vav3-overexpressing clonal cell lines, whose proliferation, invasion, and migration was then examined. Immunoblot analysis was used to investigate the activation of Akt, a Vav3 downstream target molecule. RESULTS: cDNA microarray analysis and Ingenuity pathway Analysis identified Vav3 as a hypoxia-inducible oncogene that was highly associated with malignant behavior. Vav3 messenger RNA and protein expression in LNCaP/CH cells were higher than in LNCaP/N and LNCaP cells cultured under acute hypoxia (LNCaP/AH). The growth rate of LNCaP/CH cells was lower than that of LNCaP/N cells but higher than that of LNCaP/AH cells. LNCaP/CH cells showed higher invasion and migration than LNCaP/N and LNCaP/AH cells. Interrupting Vav3 expression strongly suppressed the proliferation, invasion, and migration of LNCaP/CH cells. Furthermore, siRNA led to apoptosis with increased caspase-3 and cleaved poly (adenosine diphosphate-ribose) polymerase activation in LNCaP/CH cells. Stable Vav3 overexpression in LNCaP cells promoted cell proliferation, invasion, and migration with Akt activation. CONCLUSIONS: Our results demonstrate that Vav3 plays a crucial role in prostate cancer growth and malignant behavior, thus revealing a novel potential therapeutic target.

BACKGROUND: The Vav family of Rho/Rac guanosine nucleotide exchange factors comprises three members in mammalian cells. Vav3 enhances androgen receptor (AR) activity during progression to androgen independence in prostate cancer. We examined Vav3 small interfering RNA (siRNA) effects on cell proliferation and apoptosis in docetaxel-treated LNCaP cells under chronic hypoxia (LNCaPH). METHODS: We examined individual and combined effects of Vav3 siRNA (si-Vav3) and docetaxel on cell growth and apoptosis under chronic hypoxia by cell proliferation, flow cytometric, DNA fragmentation, and immunoblot analyses. To clarify the molecular basis of si-Vav3- and docetaxel-induced apoptosis, we analyzed alterations in phosphatidylinositol 3-kinase (PI3K)/Akt, extracellular signal-regulate kinase (ERK), c-jun N-terminal kinase (JNK), and AR pathways using kinase inhibitors in LNCaPH cells. The effects of si-Vav3/atelocollagen complex alone or in combination with docetaxel were assessed on xenografts in nude mice by tumor growth delay. RESULTS: Vav3 overexpression was observed in LNCaPH compared with the expression under normoxia. Interrupting Vav3 signaling using siRNA enhanced docetaxel-induced cell growth suppression compared with that induced by docetaxel alone by inhibition of Akt and ERK phosphorylation, resulting in AR phosphorylation inhibition. In addition to increased B-cell lymphoma 2 (Bcl-2) phosphorylation through JNK signaling in response to docetaxel, si-Vav3 enhanced docetaxel-induced apoptosis, as characterized by the accumulation of sub-G1 phase cells and DNA fragmentation, through Bcl-xL/Bcl-2-associated death promoter (Bad) dephosphorylation, resulting in increased caspase-9, caspase-3, and cleaved poly(ADP-ribose) polymerase activation. Xenograft tumor growth was slightly inhibited by si-Vav3/atelocollagen complex injection and combined use of si-Vav3/atelocollagen complex and docetaxel produced a greater effect than docetaxel alone. CONCLUSIONS: Interrupting Vav3 signaling enhances docetaxel-induced apoptosis in LNCaP cells under chronic hypoxia by inhibiting the PI3K/Akt, ERK, and AR signaling pathways. Therapy targeting Vav3 in combination with docetaxel may have practical implications for managing castration-resistant prostate cancer.

Although colorectal cancer (CRC) is one of the most common malignancies worldwide, the current therapeutic approaches for advanced CRC are ineffective. In this study, we investigated the involvement of the VAV3 oncogene in tumor progression and in the prognosis of human CRC. The two patient cohorts in this study comprised 354 CRC cases from 1998 to 2005 with documented pathologic and clinical factors and clinical outcomes. VAV3 protein levels were significantly correlated with the depth of invasion (P = 0.0259), the nodal status (P < 0.0001), distant metastasis (P = 0.0354), the stage (P < 0.0001), and poor disease-free survival (P = 0.003). Multivariate Cox regression analysis showed that VAV3 overexpression is an independent prognostic marker for CRC (P = 0.041). In vitro experiments indicated that VAV3 knockdown inhibited CRC cell growth, spread, and xenograft proliferation. Mechanistic studies further revealed that VAV3 overexpression could dysregulate the expression of cell cycle control- and metastasis-related molecules by activating the PI3K-AKT signaling pathway in both CRC cells and xenografts. This study suggests that VAV3 overexpression could be a useful marker for predicting the outcomes of CRC patients and that VAV3 targeting represents a potential modality for treating CRC.

The VAV proteins VAV1, VAV2 and VAV3 have been identified as important molecules in tumorigenesis, tumor growth and cell migration. In addition to the full-length isoforms, a much shorter family member, VAV3.1, also known as VAV3 isoform 2, is known to be differentially expressed in a broad variety of tissues. Furthermore, VAV3.1 was shown to be down-regulated in cultured keratinocytes by the growth factors epidermal growth factor (EGF) EGF and transforming growth factor beta (TGFbeta) TGFbeta which in turn play important roles in the pathogenesis of oral squamous cell carcinoma (OSCC). Herein we showed that VAV3.1 is underexpressed in OSCC tissue samples compared to corresponding normal mucosa. We further demonstrated a trend of distinctive down-regulation of mRNA for VAV3.1 in tissues of locally advanced OSCC that have already metastasized to regional lymph nodes, indicating an increased malignant potential of tumors with low VAV3.1 mRNA expression. Moreover, in other studies a correlation between increased VAV3 expression and cancer progression was shown. In the present study, the analyzed OSCC tissue samples showed no significant change of VAV3 mRNA expression. Taken together, our data support the hypothesis that molecular interactions and signaling cascades of VAV3 can be regulated or directed by the competing molecule VAV3.1. Additionally, discrete and different functions of VAV3.1 in metastasis and tumorigenesis are conceivable.

The Vav3 oncogene is overexpressed and has a significant role in the tumorigenesis of prostate cancer and glioblastoma. In the present study, the expression status and prognostic value of Vav3 expression was investigated in breast cancer. Vav3 protein levels were analyzed by immunoblotting in human breast cancer and epithelial cell lines. Immunohistochemistry was used to detect Vav3 in a tissue microarray of 173 breast cancers and 19 benign breast lesions. Statistical analysis was performed to reveal the association between Vav3 expression and clinicopathological parameters. disease-free survival (DFS) and overall survival (OS) were calculated by Kaplan-Meier analysis and the Cox regression model. The Vav3 protein level was higher in the breast cancer cell lines than in the normal human breast cells. Vav3 was expressed in 86.1% of breast cancer patients, but in only 15.6% patients with benign breast disease. Patients with negative estrogen receptor expression, axillary lymph node involvement and a high tumor-node-metastasis stage demonstrated a higher positive rate of Vav3 expression. The Kaplan-Meier survival analysis revealed that patients with higher Vav3 expression exhibited shorter DFS and OS times. The multivariate Cox analysis revealed that Vav3 was a prognostic factor of survival. Overall, Vav3 was overexpressed in human breast cancer cells and this correlated with a shorter survival time, indicating that Vav3 is a biomarker of a poor prognosis for breast cancer patients.

Scr homology 3 (SH3) domain-mediated protein-protein interactions have been implicated in the localization of proteins to specific sites within the cell. We present evidence that the product of the vav proto-oncogene, p95vav, interacts specifically with the focal adhesion protein zyxin both in vitro and in yeast two hybrid system. Solution binding and two-hybrid system experiments demonstrate that association of Vav with the LIM domain protein zyxin is mediated by the C-terminal SH3 domain of the Vav and involves the proline-rich N-terminus of zyxin. The interaction appears to be selective, since no binding of the proline-rich N-terminus of zyxin with other SH3 domain-containing proteins such as GRB-2, phospholipase C gamma, GTPase-activating protein, or p85 was detected.