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Reddy, Kaladhar B.

doi:10.1023/a:1023781114568

Cited by 466 publications

(141 citation statements)

References 85 publications

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“…The principal finding of this study is that TGF-␤1 up-regulates uPA expression in HRA and SKOv-3 cells and facilitates invasiveness through Src-dependent MAPK and PI3K/Akt activation. Involvement of Src, ERK1/2, or PI3K in invasiveness and metastatic development has been established in many neoplastic cells including HRA cells (28). Cell spreading and invasion are prevented by the pharmacological inhibitors for these kinases (29).…”

Section: Discussionmentioning

confidence: 99%

Transforming Growth Factor-β1-dependent Urokinase Up-regulation and Promotion of Invasion Are Involved in Src-MAPK-dependent Signaling in Human Ovarian Cancer Cells

Tanaka

Kobayashi

Suzuki

et al. 2004

Journal of Biological Chemistry

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Urokinase-type plasminogen activator (uPA) has been implicated in tumor cell invasion and metastasis. We reported previously that transforming growth factor (TGF)-␤1 induces a dose-and time-dependent up-regulation of uPA mRNA and protein in highly invasive human ovarian cancer cell line HRA, leading to invasion. To further elucidate the mechanism of the invasive effect of TGF-␤1, we investigated which signaling pathway transduced by TGF-␤1 is responsible for this effect. Here, we show that 1) nontoxic concentrations of TGF-␤1 activated Src kinase; 2) TGF-␤1 rapidly phosphorylates ERK1/2 and Akt, but not p38; 3) pharmacological Src inhibitor PP2 or antisense (AS) c-Src oligodeoxynucleotide (ODN) treatment reduced TGF-␤1-induced phosphorylation of ERK1/2 and Akt by 85-90% compared with controls; 4) pharmacological inhibition of MAPK by PD98059 abrogated TGF-␤1-mediated Akt stimulation, whereas TGF-␤1-induced ERK1/2 stimulation was not inhibited by PI3K inhibitor LY294002 or AS-PI3K ODN transfection; 5) up-regulation of uPA mRNA in response to TGF-␤1 was almost totally blocked by PP2 and PD98059 and partially (ϳ55%) by LY294002; 6) TGF-␤1-induced uPA mRNA up-regulation was inhibited by treatment with AS ODNs to c-Src or PI3K by 90 or 60%, respectively, compared with control ODN treatment; and 7) blockade of the release of the transcription factor NF-B by pyrrolidinedithiocarbamate reduced the TGF-␤1-induced activation of the uPA gene by ϳ65%. In addition, curcumin, a blocker of the transcriptional factor AP-1, partially (35%) canceled this effect. Taken together, these data support a role for TGF-␤1 activation of two distinct pathways (Src-MAPK-PI3K-NF-B-dependent and Src-MAPK-AP-1-dependent) for TGF-␤1-dependent uPA up-regulation and promotion of invasion.The processes of ovarian cancer dissemination are characterized by altered local proteolysis, cellular proliferation, cell attachment, and invasion, suggesting that the urokinase-type plasminogen activator (uPA) 1 could be involved in the pathogenesis of peritoneal dissemination (1). uPA is a serine protease associated with various pathological conditions including tumor invasion and metastasis (2). One of the factors regulating the metastatic process is considered to be transforming growth factor-␤ (TGF-␤), which is a multifunctional cytokine that elicits numerous cellular effects pertinent to the metastatic process (1). TGF-␤ regulates a wide range of physiological and pathological cellular processes, including cell growth, differentiation, invasion, migration, mesenchymal transition, extracellular matrix synthesis, and cell death in many cell types including ovarian cancer cells (3). Recent data demonstrated that TGF-␤ specifically stimulates up-regulation of uPA mRNA and protein in certain types of neoplastic cells (1). The cellular mechanism(s) of the TGF-␤-induced uPA-dependent tumor invasion and metastasis has been extensively studied. The identity of the signaling pathway(s) involved in the TGF-␤-induced uPA up-regulation (4) remains less known. In a well...

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Section: Discussionmentioning

confidence: 99%

Transforming Growth Factor-β1-dependent Urokinase Up-regulation and Promotion of Invasion Are Involved in Src-MAPK-dependent Signaling in Human Ovarian Cancer Cells

Tanaka

Kobayashi

Suzuki

et al. 2004

Journal of Biological Chemistry

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“…1, A and B). Active ERK signaling is reported to be essential for tumor metastasis progression including cell migration (9), suggesting that the mp53 depletion-induced migration was likely caused by the up-regulated ERK signaling. We further stably introduced mutant p53 R175H with a mutation in its DNA-binding domain into the p53-null human prostate cancer cell line PC-3 (PC-3/mp53).…”

Section: Mutant P53 Inhibits Cell Migration and Down-regulates Erk Simentioning

confidence: 99%

“…The integration of TGF-␤-mediatedSmad-dependent and -independent signaling is believed to contribute to the key events of TGF-␤-induced tumor progression including ERK signaling-mediated cell migration (8,9). TGF-␤ activates Ras/ERK signaling through the direct phosphorylation of the adaptor protein ShcA (10).…”

mentioning

confidence: 99%

Mutant p53 Disrupts Role of ShcA Protein in Balancing Smad Protein-dependent and -independent Signaling Activity of Transforming Growth Factor-β (TGF-β)

Lin

Yang

et al. 2011

Journal of Biological Chemistry

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“…The ERK-1/2 (p42/44 MAP kinase) pathway is a well characterized pathway controlling proliferation that is also implicated in transformation, invasion, tumor progression, and metastatic processes (55,56). First, we examined the constitutive activation state of Met-1/pBABE and Met-1/Cav-1 cells in complete medium (DMEM ϩ 10% serum) and found no alterations in the constitutive activation state of ERK-1/2 (data not shown).…”

Section: Cav-1 Expression In Metastatic Mammary Tumor Cells Inhibits mentioning

confidence: 99%

Caveolin-1 Gene Disruption Promotes Mammary Tumorigenesis and Dramatically Enhances Lung Metastasis in Vivo

Williams

Medina

Badano

et al. 2004

Journal of Biological Chemistry

273

214

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Caveolin-1 (Cav-1) is the principal structural component of caveolae membrane domains in non-muscle cells, including mammary epithelia. There is now clear evidence that caveolin-1 influences the development of human cancers. For example, a dominant-negative mutation (P132L) in the Cav-1 gene has been detected in up to 16% of human breast cancer samples. However, the exact functional role of caveolin-1 remains controversial. Mechanistically, in cultured cell models, Cav-1 is known to function as a negative regulator of the Rasp42/44 MAP kinase cascade and as a transcriptional repressor of cyclin D1 gene expression, possibly explaining its in vitro transformation suppressor activity. Genetic validation of this hypothesis at the in vivo and whole organismal level has been prevented by the lack of a Cav-1 (؊/؊)-null mouse model. Here, we examined the role of caveolin-1 in mammary tumorigenesis and lung metastasis using a molecular genetic approach. We interbred a well characterized transgenic mouse model of breast cancer, MMTV-PyMT (mouse mammary tumor virus-polyoma middle T antigen), with Cav-1 (؊/؊)-null mice. Then, we followed the onset and progression of mammary tumors and lung metastases in female mice over a 14-week period. Interestingly, PyMT/Cav-1 (؊/؊) mice showed an accelerated onset of mammary tumors, with increased multiplicity and tumor burden (ϳ2-fold). No significant differences were detected between PyMT/ Cav-1 (؉/؉) and PyMT/Cav-1 (؉/؊) mice, indicating that complete loss of caveolin-1 is required to accelerate both Caveolin-1 (Cav-1) 1 was first discovered as a tyrosine-phosphorylated target in Rous sarcoma virus (RSV)-transformed avian fibroblasts, suggesting a possible role for this protein in cellular transformation (1). Subsequent studies identified caveolin-1 as a component of plasma membrane caveolae, small 50 -100-nm omega-shaped invaginations involved in vesicular trafficking and cholesterol homeostasis (2, 3). Analysis of its protein expression pattern revealed that Cav-1 is found in a diverse range of cell types, including adipocytes, fibroblasts, endothelial cells, smooth muscle cells, and mammary epithelial cells (4 -7). It is now clear that the majority of caveolae require caveolin-1 for proper formation, indicating that Cav-1 is a requisite caveolar structural protein. For example, Cav-1

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Untitled

Cited by 466 publications

References 85 publications

Transforming Growth Factor-β1-dependent Urokinase Up-regulation and Promotion of Invasion Are Involved in Src-MAPK-dependent Signaling in Human Ovarian Cancer Cells

Transforming Growth Factor-β1-dependent Urokinase Up-regulation and Promotion of Invasion Are Involved in Src-MAPK-dependent Signaling in Human Ovarian Cancer Cells

Mutant p53 Disrupts Role of ShcA Protein in Balancing Smad Protein-dependent and -independent Signaling Activity of Transforming Growth Factor-β (TGF-β)

Caveolin-1 Gene Disruption Promotes Mammary Tumorigenesis and Dramatically Enhances Lung Metastasis in Vivo

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