Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P31749 (AKT)
 22,954 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Inactivating mutations in the PTEN tumor suppressor gene occur in approximately 30-50% of endometrial carcinomas. PTEN is a phosphatase that negatively regulates the phosphoinositide 3-kinase signaling pathway, including the downstream effector AKT. To evaluate the role of PTEN in endometrial growth regulation, we expressed wild-type or mutant PTEN in endometrial carcinoma cell lines. As expected, expression of exogenous PTEN decreased levels of activated AKT in all cell lines examined. However, PTEN induced a G(1) cell cycle arrest specifically in endometrial carcinoma cells that lack endogenous wild-type PTEN. Growth of cells containing wild-type PTEN was unaffected by exogenous PTEN expression. Growth arrest required a functional phosphatase domain but not the PDZ interaction motif of PTEN. Overall levels of CIP/KIP and INK4 family members, the known inhibitory regulators of the G(1) phase of the cell cycle, were unchanged. However, PTEN induced a specific reduction of cyclin D3 levels and an associated increase in the amount of the inhibitor p27(KIP1) complexed with CDK2. Enforced expression of cyclin D3 abrogated the PTEN-induced cell cycle arrest. Although PTEN signaling directly regulates p27(KIP1) levels in some settings, in endometrial carcinoma cells, PTEN expression indirectly regulated p27(KIP1) activity by modulating levels of cyclin D3. These data support multiple mechanisms of PTEN-induced cell cycle arrest.
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PMID:PTEN induces G(1) cell cycle arrest and decreases cyclin D3 levels in endometrial carcinoma cells. 1138 92

p21(Cip1/WAF1) (p21), a p53-inducible protein, is a critical regulator of cell cycle and cell survival. p21 binds to and inhibits both the DNA synthesis regulator proliferating cell nuclear antigen and cyclin A/E-CDK2 complexes. Recently, p21 has also been shown to be a positive regulator of cell cycle progression as p21 is necessary for the assembly and activation of cyclin D1-CDK4/6 complexes. Furthermore, elevated p21 protein levels have been observed in various aggressive tumors as well as linked to chemoresistance. Here we demonstrate that p21 is directly phosphorylated by AKT/PKB, a survival kinase that is hyperactivated in many late stage tumors. Two sites (Thr(145) and Ser(146)) in the carboxyl terminus of p21 are phosphorylated by AKT/PKB in vitro and in vivo. Phosphorylation of Thr(145) inhibits PCNA binding, whereas phosphorylation of Ser(146) significantly increases p21 protein stability. Glioblastoma cell lines with activated AKT/PKB show enhanced p21 stability, and they are more resistant to taxol-mediated toxicity. Finally, AKT/PKB controls the assembly of cyclin D1-CDK4 complexes through modulation of p21 and cyclin D1 levels. These data imply that enhanced levels of p21 in tumors are due, in part, to phosphorylation by activated AKT/PKB. Furthermore, they suggest that one mechanism of AKT/PKB regulation of tumor cell survival and/or proliferation is to stabilize p21 protein.
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PMID:AKT/PKB phosphorylation of p21Cip/WAF1 enhances protein stability of p21Cip/WAF1 and promotes cell survival. 1175 12

Epidermal growth factor receptor (EGFR) activation is absolutely required for cervical cell proliferation. This suggests that EGFR-inhibitory agents may be of therapeutic value. In the present study, we investigated the effects of epigallocatechin-3-gallate (EGCG), a bioactive green tea polyphenol, on EGFR signaling in cervical cells. EGCG inhibits epidermal growth factor-dependent activation of EGFR, and EGFR-dependent activation of the mitogen-activated protein kinases ERK1/2. EGCG also inhibits EGFR-dependent AKT activity. The EGCG-dependent reduction in ERK and AKT activity is associated with reduced phosphorylation of downstream substrates, including p90RSK, FKHR, and BAD. These changes are associated with increased p53, p21(WAF-1), and p27(KIP-1) levels, reduced cyclin E level, and reduced CDK2 kinase activity. Consistent with these findings, flow cytometry and TUNEL (terminal deoxynucleotidyl-transferase-mediated dUTP nick end labeling) staining revealed EGCG-dependent G(1) arrest. Moreover, sustained EGCG treatment caused apoptotic cell death. In addition to inhibiting EGFR, cell-free studies demonstrated that EGCG directly inhibits ERK1/2 and AKT, suggesting that EGCG acts simultaneously at multiple levels to inhibit EGF-dependent signaling. Importantly, the EGCG inhibition is selective, as EGCG does not effect the EGFR-dependent activation of JNK. These results suggest that EGCG acts to selectively inhibit multiple EGF-dependent kinases to inhibit cell proliferation.
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PMID:Epigallocatechin-3-gallate inhibits epidermal growth factor receptor signaling pathway. Evidence for direct inhibition of ERK1/2 and AKT kinases. 1470 54

Recent studies have shown that selective cyclooxygenase-2 (COX-2) inhibitors induce growth inhibition and cell cycle arrest in hepatocellular carcinoma (HCC) cell lines. However, the mechanism by which COX-2 inhibitors regulate the cell cycle and whether or not growth signal pathways are involved in the growth inhibition remain unclear. In this study, we investigated the mechanisms of growth inhibition and cell cycle arrest by etodolac, a selective COX-2 inhibitor, in HCC cell lines, HepG2 and PLC/PRF/5, by studying cell cycle regulatory proteins, and the MAP kinase and PDK1-PKB/AKT signaling pathways. Etodolac inhibited growth and PCNA expression and induced cell cycle arrest in both HCC cell lines. Etodolac induced p21WAF1/Cip1 and p27Kip1 expression and inhibited CDK2, CDK4, CDC2, cyclin A and cyclin B1 expression, but did not affect cyclin D1 or cyclin E. HGF and 10% FBS induced ERK phosphorylation, but phosphorylation of p38, JNK and AKT was down-regulated by etodolac. PD98059, a selective inhibitor of ERK phosphorylation, induced growth inhibition, the expression of p27Kip1 and cell cycle arrest. In conclusion, p21WAF1/Cip1, p27Kip1, CDK2, CDK4, CDC2, cyclin A, cyclin B1 and the MAP kinase signaling pathway are involved in growth inhibition and cell cycle arrest by a selective COX-2 inhibitor in HCC cell lines.
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PMID:Involvement of cell cycle regulatory proteins and MAP kinase signaling pathway in growth inhibition and cell cycle arrest by a selective cyclooxygenase 2 inhibitor, etodolac, in human hepatocellular carcinoma cell lines. 1529 30

This study delineates the antiproliferative activities and in vivo efficacy of YC-1 [3-(5'-hydroxymethyl-2'-furyl)-1-benzyl indazole] in human hepatocellular carcinoma cells. YC-1 inhibited the growth of HA22T and Hep3B cells in a concentration-dependent manner without significant cytotoxicity. YC-1 induced G(1) phase arrest in the cell cycle, as detected by an increase in the proportion of cells in the G(1) phase using FAC-Scan flow cytometric analysis. It was further shown that cGMP, p42/p44 mitogen-activated protein kinase, or AKT kinase-mediated signaling pathways did not contribute to the YC-1-induced effect. Of note, YC-1 induced a dramatic increase in the expression of cyclin-dependent kinase (CDK)-inhibitory protein, p21(CIP1/WAP1), and a modest increase in p27(KIP1). The association of p21(CIP1/WAP1) with CDK2 was markedly increased in cells responsive to YC-1. YC-1 did not modify the expression of cyclin D1, cyclin E, CDK2, or CDK4. In a corollary in vivo study, YC-1 induced dose-dependent inhibition of tumor growth in mice inoculated with HA22T cells. Immunohistochemical analysis revealed an inverse relationship between the staining of p21(CIP1/WAF) and the staining of Ki-67, a cell proliferation marker. Based on the results reported herein, we suggest that YC-1 induces cell cycle arrest and inhibits tumor growth both in vitro and in vivo via the up-regulation of p21(CIP1/WAP1) expression in HA22T cells. Because of this, YC-1 is a potential antitumor agent worthy of further investigation.
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PMID:YC-1 [3-(5'-Hydroxymethyl-2'-furyl)-1-benzyl Indazole] exhibits a novel antiproliferative effect and arrests the cell cycle in G0-G1 in human hepatocellular carcinoma cells. 1552 95

Prostate cancer (PCA) is the most common invasive malignancy and the second leading cause of cancer-related deaths in the US male population. One approach to control this malignancy is its preventive intervention by dietary agents. Inositol hexaphosphate (IP6), a dietary constituent, has shown promising efficacy against various cancers; however, limited studies have been performed with IP6 against PCA. Here, we investigated the growth-inhibitory effect and associated mechanisms of IP6 in androgen-dependent human prostate carcinoma LNCaP cells. IP6 treatment of cells resulted in a strong growth inhibition and an increase in G1 cell population. In mechanistic studies, IP6 resulted in an increase in cyclin-dependent kinase inhibitors (CDKIs) Cip1/p21 and Kip1/p27 levels, together with a decrease in cyclin-dependent kinase (CDK) 4 and cyclin D1 protein levels. An increase in CDKI levels by IP6 also led to a concomitant increase in their interactions with CDK2 and CDK4, together with a strong decrease in the kinase activity of both CDKs. Downstream in CDKI-CDK-cyclin cascade, consistent with its inhibitory effect on CDK kinase activity, IP6 treatment of cells increased hypophosphorylated levels of retinoblastoma (Rb) with a decrease in Rb phosphorylation at serine 780, 807, and 811 sites, and caused a moderate to strong decrease in the levels of transcription factors E2F1, E2F4, and E2F5. In other studies, IP6 caused a dose- and a time-dependent apoptotic death of LNCaP cells, and a decrease in Bcl2 levels, causing a strong increase in Bax versus Bcl2 ratio, as well as an inhibition of constitutively active AKT phosphorylation. Taken together, these molecular alterations provide an insight into IP6-caused growth inhibition, G1 arrest, and apoptotic death of human prostate carcinoma LNCaP cells. Because early clinical PCA growth is an androgen-dependent response, the results of the present study employing androgen-dependent LNCaP cells suggest that IP6 has promise and potential to be effective against PCA.
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PMID:Inositol hexaphosphate inhibits growth and induces G1 arrest and apoptotic death of androgen-dependent human prostate carcinoma LNCaP cells. 1554 74

Glial progenitors from the brain of normal adult Sprague-Dawley rats were compared to their initiated and malignant counterparts that were isolated from apparently normal brains of animals exposed to methylnitrosourea (MNU). Fibroblast growth factor-2 (FGF-2) or platelet-derived growth factor (PDGF)-A or -B induced differentiation of normal progenitors to a pro-astrocytic or oligodendrocytic morphology, respectively, whereas the combination of these factors resulted in their terminal differentiation to oligodendrocytes and senescence. In contrast, initiated progenitors did not exit the cell cycle when stimulated with PDGF and/or FGF-2. cDNA oligoarray analysis and RT-PCR verification showed an early upregulation/ induction of growth factor/receptors, PDGF-A, PDGFR-beta, IGFR-1, IGF-1 and -2, IL-6, MEGF-5, FRAG-1, IRS-2, HSPG, and FGFR-1, followed by a late increase in the expression IGFBP-6, PDGF-alpha, FGFR-4A, c/ERB-A, and FGFR-4, 2, and 1 during the tumorigenic progression. Western blot analyses demonstrated that MNU exposure caused progressive reduction of p21 protein levels, an increase of Rb phosphorylation, activation of AKT and CDK2, and upregulation of FGF receptors. Double immunofluorescence labeling showed progressive increase in nuclear colocalization of FGFR1, 2, and 4, which peaked in malignant lines. It is postulated that transition of normal rat glial progenitors to an initiated state is driven by IGF-1 and 2, IL-6, and the upregulation of the receptors PDGFR-beta and FGFR-1, 2, and 4. Deregulation of the cell cycle in this state involves reduction of p21 protein, concomitant upregulation of CDC2, and an increase in Rb phosphorylation that favors expression and nuclear translocation of FGFR-4 and FRAG-1 and 2. These events are associated with progressive activation of AKT and RAS. Malignant transformation is enhanced by near elimination of p21 and PC3, induction of AP-1 (upregulation of JUN-B, c-JUN, FRA-1), activation of the NF-kB pro-survival pathway, and inhibition of the TGF-beta pro-apoptotic pathway possibly in response to changes in the expression of nerve growth factor (NGF) I-A and NGFI-B. These data demonstrate that the events leading to malignancy in the rat brain in response to MNU treatment are to a great extent similar to those described for secondary glial malignancies in humans.
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PMID:Physiology and gene expression characteristics of carcinogen-initiated and tumor-transformed glial progenitor cells derived from the CNS of methylnitrosourea (MNU)-treated Sprague-Dawley rats. 1558 Nov 86

Anti-HER2 antibody trastuzumab is emerging as a frontline therapy for patients with metastatic breast cancers that overexpress HER2. Understanding the molecular mechanisms by which the antibody inhibits tumor growth should permit the design of even more effective trastuzumab-based protocols. Several groups including our own have demonstrated that induction of cyclin-dependent kinase (CDK) inhibitor p27Kip1 protein is one of the key mechanisms of action of HER2-targeting antibodies. In this review, we discuss currently available data regarding the multiple signaling targets and pathways by which HER2-targeting antibodies upregulate p27Kip1 protein in breast cancer cells that overexpress HER2. Anti-HER2 antibodies inhibit HER2-mediated signaling in cancer cells, ultimately upregulating the levels and activity of p27Kip1 protein. At least six signaling targets and pathways are modulated by trastuzumab. By inhibiting CDK2 and decreasing Thr187 phosphorylation of p27Kip1, trastuzumab abrogates targeting of SCF-ubiquitin E3 ligase and minimizes proteasome degradation of p27Kip1. By inhibiting AKT and human kinase interacting stathmin (hKIS), trastuzumab blocks Thr157-, Thr198- and Ser10-induced p27Kip1 translocation from the nucleus to the cytosol, which increases the inhibitory effect of p27Kip1. By inhibiting Jun activation domain-binding protein 1 (Jab1) trastuzumab increases nuclear retention of p27Kip1. By inhibiting cyclin D and c-Myc, trastuzumab releases the sequestrated p27bKip1 protein from cyclin D-CDK4/6 complexes and increase the effect of p27Kip1 on CDK2-cyclin E complexes. By stimulating minibrain related kinase (MIRK), trastuzumab stabilizes p27Kip1 in the nucleus, which increases inhibitory action of p27Kip1 on CDK2. The targets and pathways affected by trastuzumab work in concert to maximize the expression and inhibitory effect of p27Kip1, which leads to cell cycle G1 arrest and growth inhibition.
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PMID:HER2-targeting antibodies modulate the cyclin-dependent kinase inhibitor p27Kip1 via multiple signaling pathways. 1561 42

The novel synthetic retinoid 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalene carboxylic acid (CD437) induces growth arrest and apoptosis in various tumor cell lines including non-small cell lung cancer (NSCLC) cells. CD437 binds retinoic acid receptor gamma (RARgamma) selectively, and can enhance receptor-dependent transcriptional activation of various genes. However, some of the effects of this retinoid on cell growth inhibition and apoptosis appear to be receptor-independent. To gain a better understanding of the mechanism by which CD437 exerts its effects, we employed a high throughput western blotting method (PowerBlottrade mark) using 760 monoclonal antibodies to compare the levels of their target cellular signaling proteins in untreated and CD437-treated NSCLC H460 cells. CD437 (1 microM, 24 h) increased the levels of 70 proteins and decreased the levels of 28 proteins. These proteins play a role in fundamental cellular processes including: DNA synthesis and repair, transcription and DNA-binding, cell cycle, apoptosis, cytoskeleton assembly, cell adhesion, endocytosis, growth and signal transduction. Some proteins identified by this approach have been implicated previously in the effect of CD437 (e.g., p53, Bax, cyclin B, CDK2). Additionally we identified proteins that are novel candidates for mediating the cellular responses to CD437 (e.g., FAF1, Bid, caspase 8, cdk1, KAP, NDR, RBBP, 53BP2, Grb2, PLCgamma1, p70s6k, PP2Cdelta, PKBalpha/AKT, PDK1, and several DNA repair enzymes).
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PMID:Identification of protein modulation by the synthetic retinoid CD437 in lung carcinoma cells using high throughput immunoblotting. 1564 34

CDKN1B (p27) regulates cell-cycle progression at the G1-S transition by suppressing the cyclin E/CDK2 kinase complex. In normal lymphocytes and most human B cell non-Hodgkin lymphomas (NHL), there is an inverse correlation between proliferative activity and expression of p27; however, a subset of NHL with high mitotic indices expresses p27, which is inactive due to sequestration in nuclear protein complexes or due to cytoplasmic retention. Our studies of mouse B cell NHL also identified cases with high proliferative activity and high levels of p27 at a surprisingly high frequency. Here, p27 was complexed with D-type cyclins 1 and 3 and with the COPS9 protein, JAB1. In addition, we found cytoplasmic sequestration following phosphorylation by activated AKT.
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PMID:Expression of the cyclin-dependent kinase inhibitor p27 and its deregulation in mouse B cell lymphomas. 1612 98


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