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PubMed2005

Activation of the PI3K/Akt signal transduction pathway and increased levels of insulin receptor in protein repair-deficient mice.

Protein L-isoaspartate (D-aspartate) O-methyltransferase is an enzyme that catalyses the repair of isoaspartyl damage in proteins. Mice lacking this enzyme (Pcmt1-/- mice) have a progressive increase in brain size compared with wild-type mice (Pcmt1+/+ mice), a phenotype that can be associated with alterations in the PI3K/Akt signal transduction pathway. Here we show that components of this pathway, including Akt, GSK3beta and PDK-1, are more highly phosphorylated in the brains of Pcmt1-/- mice, particularly in cells of the hippocampus, in comparison with Pcmt1+/+ mice. Examination of upstream elements of this pathway in the hippocampus revealed that Pcmt1-/- mice have increased activation of insulin-like growth factor-I (IGF-I) receptor and/or insulin receptor. Western blot analysis revealed an approximate 200% increase in insulin receptor protein levels and an approximate 50% increase in IGF-I receptor protein levels in the hippocampus of Pcmt1-/- mice. Higher levels of the insulin receptor protein were also found in other regions of the adult brain and in whole tissue extracts of brain, liver, heart and testes of both juvenile and adult Pcmt1-/- mice. There were no significant differences in plasma insulin levels for adult Pcmt1-/- mice during glucose tolerance tests. However, they did show higher peak levels of blood glucose, suggesting a mild impairment in glucose tolerance. We propose that Pcmt1-/- mice have altered regulation of the insulin pathway, possibly as a compensatory response to altered glucose uptake or metabolism or as an adaptive response to a general accumulation of isoaspartyl protein damage in the brain and other tissues.

3-Phosphoinositide-Dependent Protein Kinases↗
PubMed2007

Neuroprotection of selenite against ischemic brain injury through negatively regulating early activation of ASK1/JNK cascade via activation of PI3K/AKT pathway.

AIM: To investigate whether selenite, a known antioxidant, could decrease the activation of apoptosis signal regulating kinase 1/c-jun N-terminal kinase (ASK1/ JNK) signaling cascade in cerebral ischemia/reperfusion (I/R) by activating the phosphatidylinositol 3-kinase (PI3K)/AKT pathway in rat hippocampi, and the neuroprotective effect of selenite against ischemic injury after 15 min of transient brain ischemia. METHODS: Transient global brain ischemia was induced by 4-vessel occlusion into adult male Sprague-Dawley rats weighing 250-300 g. The rats were pretreated only with selenite (0.3 mg/kg dissolved in 0.9% saline) every 24 h for 7 d by means of intravenous injection of the tail or combined with LY294002 from d 5 by left cerebral ventricle injection before surgery. RESULTS: Selenite significantly increased AKT1 activation and decreased the activation of ASK1/ JNK cascade via phosphorylating ASK1 at Ser-83 residue by AKT1 during early reperfusion after 15 min transient global brain ischemia. On the contrary, combined pretreatment of the rats with LY294002 (a specific PI3K inhibitor) and selenite significantly inhibited the effects solely with selenite. CONCLUSION: The activation of the pro-apoptotic ASK1/JNK cascade, which is closely associated with oxidative stress, could be suppressed by selenite through activating the antiapoptotic PI3K/AKT pathway during early reperfusion after cerebral ischemia in rat hippocampi.

Animals↗
PubMed2003

Putative phosphatidylinositol 3-kinase (PI3K) binding motifs in ovine betaretrovirus Env proteins are not essential for rodent fibroblast transformation and PI3K/Akt activation.

Jaagsiekte sheep retrovirus (JSRV) and enzootic nasal tumor virus (ENTV) are simple betaretroviruses that cause epithelial cell tumors in the lower and upper airways of sheep and goats. The envelope (Env) glycoproteins of both viruses can transform rodent and chicken fibroblasts, indicating that they play an essential role in oncogenesis. Previous studies found that a YXXM motif in the Env cytoplasmic tail, a putative docking site for phosphatidylinositol 3-kinase (PI3K) after tyrosine phosphorylation, was necessary for rodent cell transformation but was not required for transformation of DF-1 chicken fibroblasts. Here we show that JSRV and ENTV Env proteins with tyrosine or methionine mutations in the YXXM motif can still transform rodent fibroblasts, albeit with reduced efficiency. Akt was activated in cells transformed by JSRV or ENTV Env proteins and in cells transformed by the proteins with tyrosine mutations. Furthermore, the PI3K-specific inhibitor LY294002 could inhibit Akt activation and cell transformation in all cases, indicating that Akt activation and transformation is PI3K dependent. However, we could not detect tyrosine phosphorylation of JSRV or ENTV Env proteins or an interaction between the Env proteins and PI3K in the transformed cells. We found no evidence for mitogen-activated protein kinase activation in cells that were transformed by the JSRV or ENTV Env proteins. We conclude that ovine betaretrovirus Env proteins transform the rodent fibroblasts by indirectly activating the PI3K/Akt pathway.

3T3 Cells↗
PubMed2006

Human esophageal microvascular endothelial cells respond to acidic pH stress by PI3K/AKT and p38 MAPK-regulated induction of Hsp70 and Hsp27.

The heat shock response maintains cellular homeostasis following sublethal injury. Heat shock proteins (Hsps) are induced by thermal, oxyradical, and inflammatory stress, and they chaperone denatured intracellular proteins. Hsps also chaperone signal transduction proteins, modulating signaling cascades during repeated stress. Gastroesophageal reflux disease (GERD) affects 7% of the US population, and it is linked to prolonged esophageal acid exposure. GERD is characterized by enhanced and selective leukocyte recruitment from esophageal microvasculature, implying activation of microvascular endothelium. We investigated whether phosphatidylinositol 3-kinase (PI3K)/Akt and MAPK regulate Hsp induction in primary cultures of human esophageal microvascular endothelial cells (HEMEC) in response to acid exposure (pH 4.5). Inhibitors of signaling pathways were used to define the contribution of PI3K/Akt and MAPKs in the heat shock response and following acid exposure. Acid significantly enhanced phosphorylation of Akt and MAPKs in HEMEC as well as inducing Hsp27 and Hsp70. The PI3K inhibitor LY-294002, and Akt small interfering RNA inhibited Akt activation and Hsp70 expression in HEMEC. The p38 MAPK inhibitor (SB-203580) and p38 MAPK siRNA blocked Hsp27 and Hsp70 mRNA induction, suggesting a role for MAPKs in the HEMEC heat shock response. Thus acidic pH exposure protects HEMEC through induction of Hsps and activation of MAPK and PI3 kinase pathway. Acidic exposure increased HEMEC expression of VCAM-1 protein, but not ICAM-1, which may contribute to selective leukocyte (i.e., eosinophil) recruitment in esophagitis. Activation of esophageal endothelial cells exposed to acidic refluxate may contribute to GERD in the setting of a disturbed mucosal squamous epithelial barrier (i.e., erosive esophagitis, peptic ulceration).

Actins↗
PubMed2004

ERK, PKC and PI3K/Akt pathways mediate extracellular ATP and adenosine-induced proliferation of U138-MG human glioma cell line.

OBJECTIVE: Extracellular nucleotides and nucleosides induce proliferation in a set of human glioma cell lines. In this study we investigate the signal transduction pathways involved in ATP and adenosine-mediated proliferation in U138-MG human glioma cells. METHODS: Cell proliferation was accessed through [(3)H]thymidine incorporation, cell counting and flow cytometry. Protein phosphorylation was detected through Western blotting. RESULTS: ATP or adenosine (100 microM) induced extracellular signal-regulated protein kinase (ERK), Akt and GSK3beta phosphorylation. The increase in [(3)H]thymidine incorporation induced by ATP or adenosine was decreased when cells were incubated with LY 294002 (by +/-90%), GF 109203X (by +/-76%) or PD 098059 (by +/-63%). The increase in cell numbers with ATP or adenosine was less after a 48-hour treatment of cells with ATP or adenosine plus GF 109203X (by +/-66%) or LY 294002 (by +/-83%). Percentage of cells in S phase was decreased in cells treated with LY 294002 plus ATP when compared to ATP- treated cells. CONCLUSION: Stimulation of purinergic receptors in U138-MG cells leads to cell proliferation mediated by PI3K/Akt, ERK and PKC signaling. It may be clinically important for pharmacological intervention in gliomas to associate purinergic receptor antagonists and signal transduction pathways blockers.

Adenosine↗
PubMed2005

PI3K/AKT signaling and systemic autoimmunity.

The phosphoinositide 3-kinase (PI3K)/Akt signaling axis plays an important role in cellular proliferation and growth signaling. With respect to the immune system, a growing body of data is helping to elucidate the role of this pathway in lymphocyte development, as well as to show how perturbations that lead to unregulated activation in this pathway may produce systemic autoimmunity or malignancy. Various knockout and transgenic murine models have been described for key mediators of this signaling pathway. Many of these models resulting in the activation of this pathway demonstrate features of systemic autoimmunity, linking this pathway to autoimmune disease. Here, we review recently described murine models that exhibit activated PI3K/Akt signaling and the potential role this pathway in autoimmune disease, and also discuss the therapeutic implications of these findings.

Animals↗
PubMed2026

Inhibition of MAFB and PI3K/AKT Signaling for Hereditary FSGS with Multicentric Carpotarsal Osteolysis.

KEY POINTS: Multicentric carpotarsal osteolysis, a rare disorder, causes progressive osteolysis and kidney failure because of v-maf avian musculoaponeurotic fibrosarcoma oncogene homolog B (MAFB) gene mutations. A genome-edited mouse model carrying the multicentric carpotarsal osteolysis mutation was used to obtain a deeper understanding of this rare disease. Targeting MAFB/IGF-1/PI3K/AKT signaling may provide new treatments for multicentric carpotarsal osteolysis-related nephropathy. BACKGROUND: Multicentric carpotarsal osteolysis (MCTO) is a rare condition characterized by progressive osteolysis and often kidney failure. It is caused by autosomal dominant mutations in the transcription factor v-maf avian musculoaponeurotic fibrosarcoma oncogene homolog B ( MAFB ). METHODS: Given the absence of efficacious therapeutic interventions for MCTO and the obscurity of its pathophysiologic mechanisms, we used mice with the MCTO mutation ( MafbMCTO/MCTO mice) to explore the role of MAFB. RESULTS: MafbMCTO/MCTO mice displayed FSGS, mirroring the manifestations seen in patients with MCTO. These mice showed that the MCTO mutation leads to the accumulation of MAFB protein. Heterozygous MafbMCTO/- mice, generated by crossbreeding to reduce MAFB levels, neither exhibited albuminuria nor showed any histologic abnormalities in the kidney, suggesting that excess MAFB was detrimental. We subsequently conducted RNA-seq on the glomeruli from MafbMCTO/MCTO mice and detected pronounced upregulation of the phosphoinositide 3-kinase (PI3K)/AKT signaling pathway through IGF-1. Given that receptor tyrosine kinases activate PI3K/AKT, we treated MafbMCTO/MCTO mice with the inhibitor imatinib. This led to a significant decline in urinary albumin levels compared with the control group. CONCLUSIONS: Our findings demonstrate that the MCTO mutation resulted in MAFB protein accumulation and led to the development of FSGS in mice.

Animals↗
PubMed2005

Involvement of PI3K/Akt pathway in prostate cancer--potential strategies for developing targeted therapies.

This review presents some therapeutic interventions actually considered in prostate cancer therapy to compensate constitutive activation of the PI3K/Akt signalling pathway induced, particularly, by mutations of PTEN gene. Special emphasis is placed on applicability of EGF-R tyrosine kinase, COX-2, PDK-1, mTOR and farnesyltransferase inhibitors.

3-Phosphoinositide-Dependent Protein Kinases↗
PubMed2004

[The effect of HER2/neu overexpression on p53 gene expression, cell proliferation and sensitivity to gamma-irradiation via the PI3K/Akt pathway in breast cancer cell MCF7].

OBJECTIVE: To investigate the effect of HER2/neu overexpression on the wild p53 gene expression, cell proliferation and sensitivity to gamma-irradiation via phosphatidylinositol 3-kinase (PI3K) pathway in human breast cancer cell MCF7. METHODS: Lipofectin-mediated gene transfection method was used to transfer HER2/neu into MCF7 cells. Expression of HER2/neu, p53, Akt and p-Akt protein after PI3K pathway inhibitor LY294002 treatment was determined by Western blot. Cell proliferation and cell surviving fraction after gamma-irradiation treatment were assayed by MTT. RESULTS: Eighteen of HER2/neu stably transfected MCF7 cell clones were established, one of them was HER2/neu overexpressing. HER2/neu overexpressing MCF7 cells showed higher p-Akt expression and lower p53 expression than those of parental MCF7 cells, which could be abrogated by LY294002. HER2/neu overexpressing MCF7 cells had higher proliferation rate and lower sensitivity to gamma-irradiation than those of parental MCF7 cells, which could be opposed by LY294002. CONCLUSION: Overexpression of HER2/neu induces reduced expression of wild-type p53 protein, relatively high cell proliferation and low sensitivity to gamma-irradiation in breast cancer cell MCF7 by activating PI3K/Akt pathway, which may contribute to therapeutic resistance in some breast cancer patients with wild-type p53 gene status.

Breast Neoplasms↗
PubMed2006

CoCl2-induced HIF-1alpha expression correlates with proliferation and apoptosis in MKN-1 cells: a possible role for the PI3K/Akt pathway.

The exact mechanism behind the effect of hypoxia-inducible factor-1alpha (HIF-1alpha) on the proliferation and/or apoptosis of carcinoma cells is still a matter of debate. We treated a human gastric carcinoma cell line, MKN-1 (mutant P53), with 500 microM CoCl(2). A dual-phase pattern of HIF-1alpha expression with an increase until 4 h followed by a decrease until 36 h was observed. Immunocytochemistry showed that nuclear translocation was maximal at 4 h of treatment, while trypan blue staining showed a dual-phase pattern. Instead of G1/S arrest, FACS showed an increase in the pre-G1 fraction and G(2)/M arrest that correlated with Cyclin-B1, SKP-2 and P27 expression. Starting at 6 h, the apoptotic index increased in a time-dependent manner, in correlation with the expression of HIF-1alpha, Bcl-2, Bcl-xL, Bax and cleaved-Caspase-9. Phosphorylation of Akt was inhibited by CoCl(2) treatment and LY294002 treatment inhibited HIF-1alpha expression in a dose-dependent manner. These results suggested that the alteration of CoCl(2)-induced HIF-1alpha expression correlated with proliferation and apoptosis in MKN-1 cells. A possible role for the PI3K/Akt pathway was indicated in this model of hypoxia.

Antimutagenic Agents↗
PubMed2004

TOR kinase and Ran are downstream from PI3K/Akt in H2O2-induced mitosis.

Hydrogen peroxide (H2O2) activates signaling cascades essential for cell proliferation via phosphatidylinositol-3-kinase (PI3K) and Akt. Here we show that induction of mitogenic signaling by H2O2 activates sequentially PI3K, Akt, mammalian target of rapamycin (mTOR), and Ran protein. Akt activation is followed by signaling through the mTOR kinase and upregulation of Ran in primary type II pneumocytes, a cell type implicated in the development of lung adenocarcinoma. Pretreatment of the cells with wortmannin, a specific inhibitor of PI3K, or rapamycin, a specific inhibitor of mTOR kinase, prevented H2O2-increased mitosis. H2O2-induced Akt ser-473 phosphorylation and upregulation of Ran protein were prevented by wortmannin but not by rapamycin, indicating that PI3K is upstream of Akt and mTOR is downstream from Akt. Overexpression of myr-Akt or Ran-wt in type II pneumocytes increased Akt ser-473 phosphorylation and mitosis in a catalase-dependent manner, indicating that H2O2 is essential for Akt and Ran signaling. These results indicate that H2O2-induced mitogenic signaling in primary type II pneumocytes is mediated by PI3K, Akt, mTOR-kinase, and Ran protein.

Androstadienes↗
PubMed2004

Down-regulation of MEK/ERK signaling by E-cadherin-dependent PI3K/Akt pathway in differentiating intestinal epithelial cells.

In vitro experiments have shown that the establishment of cell-cell contacts in intestinal epithelial cell cultures is a critical step in initiating ERK inhibition, cell cycle arrest, and induction of the differentiation process. Herein, we determined the mechanisms through which E-cadherin-mediated cell-cell contacts modulate the ERK pathway in intestinal epithelial cells. We report that: (1) removal of calcium from the culture medium of newly confluent Caco-2/15 cells (30 min, 4 mM EGTA) results in the disruption of both adherens and tight junctions and clearly decreases Akt phosphorylation while increasing MEK and ERK activities. Akt, MEK, and ERK activation levels return to control levels 60 min after calcium restoration; (2) the use of E-cadherin blocking antibodies efficiently prevents Akt phosphorylation and MEK-ERK inhibition after 70 min of calcium restoration; (3) using the PI3K inhibitor LY294002 (15 microM) in calcium switch experiments, we demonstrate that the assembly of adherens junctions activates Akt activity and triggers the inhibition of ERK1/2 activities in a PI3K-dependent manner; (4) adenoviral infection of confluent Caco-2/15 cells with a constitutively active mutant of Akt1 strongly represses ERK1/2 activities; (5) inhibition of PI3K abolishes Akt activity but leads to a rapid and sustained activation of the MEK-ERK1/2 in confluent differentiating Caco-2/15 cells, but not in undifferentiated growing Caco-2/15 cells. Our data suggest that E-cadherin engagement leads to MEK/ERK inhibition in a PI3K/Akt-dependent pathway. This mechanism may account for the role of E-cadherin in proliferation/differentiation transition along the crypt-villus axis of the human intestinal epithelium.

Caco-2 Cells↗
PubMed2006

FOXO-independent suppression of programmed cell death by the PI3K/Akt signaling pathway in Drosophila.

Signaling through the PI3K/Akt/FOXO pathway plays an important role in vertebrates in protecting cells from programmed cell death. PI3K and Akt have been similarly shown to be involved in survival signaling in the invertebrate model organism Drosophila. However, it is not known whether PI3K and Akt execute this function by controlling a pro-apoptotic activity of Drosophila FOXO. In this study, we show that elevated signaling through PI3K and Akt can prevent developmentally controlled death in the salivary glands of the fruit fly. We further show that Drosophila FOXO is not required for normal salivary gland death and that the rescue of salivary gland death by PI3K occurs independent of FOXO. These results give support to the notion that FOXOs have acquired pro-apoptotic functions after separation of the vertebrate and invertebrate lineages.

Animals↗
PubMed2006

Downregulation of the PI3K/Akt survival pathway in cells with deregulated expression of c-Myc.

Oncogenic transformation leads to an increased sensitivity to apoptosis, a characteristic that is selectively lost during tumor progression. The sensitization process affects the mitochondrial pathway of apoptosis through signaling events that are poorly defined. We previously showed that a deregulated expression of c-Myc in cells treated with toxic agents caused an enhanced activation of p38 that acts in a death-promoting pathway. Here, we show that deregulated expression of c-Myc causes a severe reduction in the basal activity of Akt, which was further accelerated by serum deprivation. Furthermore, c-Myc expression repressed the activation of Akt induced by the toxic agents doxorubicin, cisplatin and H(2)O(2), and also by the physiological agonists PDGF and insulin. We determined that the activation of Akt was inhibited as a result of the action of c-Myc upstream of phosphatidylinositol 3-kinase (PI3K) activation. c-Myc overexpression impaired the induced association of the p85 subunit of PI3K with phosphotyrosine containing proteins, causing a reduction in the activation of PI3K and recruitment of Akt to the membrane. Inhibiting Akt in addition to enhancing p38 further exacerbate the imbalance between the death and survival signals and results in an enhanced sensitivity to apoptosis.

Animals↗
PubMed2005

The neuroprotection of insulin on ischemic brain injury in rat hippocampus through negative regulation of JNK signaling pathway by PI3K/Akt activation.

Current studies demonstrated that cell survival is determined by a balance among signaling cascades, including those that recruit the Akt and JNK pathways. In our present work, the relationship between Akt1 and JNK1/2 was evaluated after cerebral ischemia-reperfusion in the hippocampus in a four-vessel occlusion model of Sprague-Dawley rats. This paper was based on our present and previous studies. Firstly, Akt1 had one active peak during reperfusion following 15 min ischemia. Secondly, two peaks of JNK1/2 activation occurred during reperfusion, respectively. Thirdly, the phosphorylation of JNK substrates c-Jun and Bcl-2, and the activation of a key protease of caspase-3 were detected. They only had one active peak, respectively, during reperfusion. To clarify the mechanism of Akt1 activation and further define whether JNK1/2 activation could be regulated by Akt1 through PI3K pathway, LY294002 and insulin were, respectively, administrated to the rats prior to ischemia. Our research indicated that LY294002, a PI3K inhibitor, significantly suppressed Akt1 activation. Furthermore, LY294002 significantly strengthened both peaks of JNK1/2 activation, c-Jun activation, Bcl-2 phosphorylation, and the activation of caspase-3 during reperfusion. In contrast, insulin, a PI3K agonist, not only obviously activated Akt1 during early and later reperfusion, but also inhibited phosphorylation of JNK1/2, c-Jun, and Bcl-2 and attenuated the activation of caspase-3. In addition, pretreatment of insulin significantly increased the number of the surviving CA1 pyramidal cells at 5 days of reperfusion. Consequently, our results indicated that the cross-talk between Akt1 and JNK1/2 could be mediated by insulin receptor through PI3K in rat hippocampus during reperfusion. This signaling pathway might play a neuroprotective role against ischemic insults via inhibition of the JNK pathway, involving the death effector of caspase-3.

Analysis of Variance↗
PubMed2006

Glial-derived neurotrophic factor (GDNF) prevents ethanol (EtOH) induced B92 glial cell death by both PI3K/AKT and MEK/ERK signaling pathways.

We investigated the neuroprotective effect of glial-derived neurotrophic factor (GDNF) upon alcohol-exposed B92 cultures, as well as the role of the cytoskeleton and mitogen-activated protein kinase (MAPK) pathways in this effect. Ethanol (EtOH) was added to cultures, either alone or in combination with 30 ng/ml GDNF. Exposure to EtOH (86 and 172 mM; 60 and 120 min) increased the frequency of apoptotic cells identified by nuclear DNA staining with 4,6-diamidino-2-phenylindole (DAPI). Cultures treated with GDNF showed a decrease in ethanol-induced apoptosis. A jun N-terminal kinase (JNK) pathway is activated by EtOH and their pharmacological inhibition (by SP600125) neutralized ethanol-induced apoptosis, suggesting a role for JNK in EtOH neurotoxicity. Immunocytochemically detected phospho-JNK (p-JNK) showed an unusual filamental expression, and localized together with actin stress fibers. Examination of the cytoskeleton showed that EtOH depolymerized actin filaments, inducing p-JNK dissociation and translocation to the nucleus, which suggests that released p-JNK may contribute to glial cell death after EtOH exposure. Treatment with GDNF, in turn, may neutralize the ethanol-induced cell death pathway. Either a phosphatidylinositol 3-kinase (PI3K)/AKT pathway inhibitor (LY294002) or an inhibitor of the extracellular signal-regulated kinase (ERK) 1, 2 pathways (UO126) failed to neutralize GDNF protective effects. However, the simultaneous use of both inhibitors blocked the protective effect of GDNF, suggesting a role for both signaling cascades in the GDNF protection. These findings provide further insight into the mechanism involved in ethanol-induced apoptosis and the neurotrophic protection of glial cells.

Actin Cytoskeleton↗
PubMed2005

ICAM-3-induced cancer cell proliferation through the PI3K/Akt pathway.

ICAM-3 interacts with LFA1, and is involved in the intercellular adhesion of leukocytes as well as in the mainenance of cell survival. It has also been suggested to induce cancer cell proliferation but the precise signaling pathway is unclear. The aim of this study was to determine the ICAM-3-activated downstream pathway in H1299 lung cancer cells. The level of ICAM-3-induced cell growth was examined using BrdU incorporation, which is a colony-forming assay, FACS analysis, and cell counting. The results showed that ICAM-3 expression induces cancer cell proliferation. In addition, FAK, Akt, PDK1, GSK-3beta, BAD, and PTEN were phosphorylated by ICAM-3-overexpression, resulting in enhanced cell proliferation. In conclusion, ICAM-3 expression induces cancer cell proliferation, and an increase in ICAM-3 expression can contribute to cancer progression.

Antigens, CD↗
PubMed2004

High tumor incidence and activation of the PI3K/AKT pathway in transgenic mice define AIB1 as an oncogene.

The gene encoding AIB1, an estrogen receptor coactivator, is amplified in a subset of human breast cancers. Here we show that overexpression of AIB1 in transgenic mice (AIB1-tg) leads to mammary hypertrophy, hyperplasia, abnormal postweaning involution, and the development of malignant mammary tumors. Tumors are also increased in other organs, including the pituitary and uterus. AIB1 overexpression increases mammary IGF-I mRNA and serum IGF-I protein levels. In addition, IGF-I receptor and downstream signaling molecules are activated in primary mammary epithelial cells and mammary tumor cells derived from AIB1-tg mice. Knockdown of AIB1 expression in cultured AIB1-tg mammary tumor cells leads to reduced IGF-I mRNA levels and increased apoptosis, suggesting that an autocrine IGF-I loop underlies the mechanism of AIB1-induced oncogenesis.

Acetyltransferases↗