Biphasic modulation of cell growth by recombinant human galectin-1

Adams, Lowell; Scott, G. K.; Weinberg, Clarice R.

doi:10.1016/0167-4889(96)00031-6

Cited by 128 publications

(115 citation statements)

References 31 publications

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“…Other galectins also induce growth arrest. Galectin-1 functions as a cytostatic factor for murine embryo fibroblasts (12,56) and galectin-3 induces cell cycle arrest of human breast epithelial cells (14), whereas galectin-12 inhibits growth of HeLa cells (13). Galectin-3-mediated G 1 arrest involves down-regulation of cyclin E and cyclin A and up-regulation of p21 and p27 (14,57), suggesting that both galctin-8 and galectin-3 induce growth arrest by a mechanism that involves the accumulation of p21.…”

Section: Discussionmentioning

confidence: 99%

Cyclin-dependent Kinase Inhibitors and JNK Act as Molecular Switches, Regulating the Choice between Growth Arrest and Apoptosis Induced by Galectin-8

Arbel-Goren

Levy

Ronen

et al. 2005

Journal of Biological Chemistry

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Galectin-8, a mammalian ␤-galactoside binding lectin, functions as an extracellular matrix protein that forms high affinity interactions with integrins. Here we demonstrated that soluble galectin-8 inhibits cell cycle progression and induces growth arrest. These effects cannot be attributed to interference with cell adhesion but can be attributed to a 4 -5-fold increase in the cellular content of the cyclin-dependent kinase inhibitor p21, which was already evident following a 4-h incubation of H1299 cells with galectin-8. The increase in p21 levels was preceded by a 3-5-fold increase in JNK and protein kinase B (PKB) activities. Accordingly, SP600125, the inhibitor of JNK, and wortmannin, the inhibitor of phosphatidylinositol 3-kinase, which is the upstream activator of PKB, inhibited the increase in the cellular content of p21. Furthermore, overexpression of a dominant inhibitory form of SEK1, the upstream kinase regulator of JNK, inhibited both JNK activation and p21 accumulation. When p21 expression was inhibited by cycloheximide, galectin-8 directed the cells toward apoptosis, which involves induction of poly(ADP-ribose) polymerase cleavage. Indeed, galectin-8-induced apoptosis was 2-fold higher in HTC (p21-null) cells when compared with parental HTC cells. Because overexpression of galectin-8 attenuates the rate of DNA synthesis, stable colonies that overexpress and secrete galectin-8 can be generated only in cells overexpressing a growth factor receptor, such as the insulin receptor. These results implicate galectin-8 as a modulator of cellular growth through up-regulation of p21. This process involves activation of JNK, which enhances the synthesis of p21, combined with the activation of PKB, which inhibits p21 degradation. These effects of the lectin depended upon protein-sugar interactions and were induced when galectin-8 was present as a soluble ligand or when it was overexpressed in cells.

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Section: Discussionmentioning

confidence: 99%

Cyclin-dependent Kinase Inhibitors and JNK Act as Molecular Switches, Regulating the Choice between Growth Arrest and Apoptosis Induced by Galectin-8

Arbel-Goren

Levy

Ronen

et al. 2005

Journal of Biological Chemistry

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“…Interestingly, it has been reported that galectin-1 exerts a biphasic modulation of cell growth. While high doses of galectin-1 inhibit cell proliferation independent of its sugarbinding activity, low doses of galectin-1 are mitogenic and are susceptible to inhibition by lactose (Adams et al, 1996). Furthermore, galectin-1 can also regulate cell cycle progression in human tumour cells (Wells et al, 1999).…”

Section: Galectin-1 In Tumour Growthmentioning

confidence: 99%

Galectin-1 as a potential cancer target

2005

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Galectins are a family of structurally related carbohydrate-binding proteins, which are defined by their affinity for poly-Nacetyllactosamine-enriched glycoconjugates and sequence similarities in the carbohydrate recognition domain. Galectin-1, a member of this family, contributes to different events associated with cancer biology, including tumour transformation, cell cycle regulation, apoptosis, cell adhesion, migration and inflammation. In addition, recent evidence indicates that galectin-1 contributes to tumour evasion of immune responses. Given the increased interest of tumour biologists and clinical oncologists in this field and the potential use of galectins as novel targets for anticancer drugs, we summarise here recent advances about the role of galectin-1 in different events of tumour growth and metastasis.

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“…Its widespread differential expression in malignant cells and their non-transformed counterparts raises the possibility that Gal-1 also functions as a modulator of proliferation in other cell types, such as epithelial cells. Indeed, growth inhibition of tumor cells by Gal-1 has been reported (10,11). Of note, these growth effects were unaffected by the presence of a glycan inhibitor (9) or not specified with respect to glycan inhibitors (11), whereas the proapoptotic action of galectins on activated T-cells clearly depended on ␤-galactoside-specific binding (12).…”

mentioning

confidence: 97%

Galectin-1 Interacts with the α5β1 Fibronectin Receptor to Restrict Carcinoma Cell Growth via Induction of p21 and p27

Fischer

Sanchez-Ruderisch

Welzel

et al. 2005

Journal of Biological Chemistry

154

126

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Surface binding of galectin family members has the potential to link distinct glycan structures to growth regulation. Therefore, we addressed the antiproliferative potential of galectin-1 (Gal-1) in a panel of carcinoma cell lines. We discovered growth inhibition by Gal-1 in epithelial tumor cell lines from different origins and provide evidence that this effect requires functional interaction with the ␣5␤1 integrin. Antiproliferative effects result from inhibition of the Ras-MEK-ERK pathway and consecutive transcriptional induction of p27. We have further identified two Sp1-binding sites in the p27 promoter as crucial for Gal-1 responsiveness. Inhibition of the Ras-MEK-ERK cascade by Gal-1 increased Sp1 transactivation and DNA binding due to reduced threonine phosphorylation of Sp1. Furthermore, Gal-1 induced p21 transcription and selectively increased p27 protein stability. Gal-1-mediated accumulation of p27 and p21 inhibited cyclin-dependent kinase 2 activity and ultimately resulted in G 1 cell cycle arrest and growth inhibition. These data define a novel mechanism whereby Gal-1 regulates epithelial tumor cell homeostasis via carbohydrate-dependent interaction with the ␣5␤1 integrin.

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Biphasic modulation of cell growth by recombinant human galectin-1

Cited by 128 publications

References 31 publications

Cyclin-dependent Kinase Inhibitors and JNK Act as Molecular Switches, Regulating the Choice between Growth Arrest and Apoptosis Induced by Galectin-8

Cyclin-dependent Kinase Inhibitors and JNK Act as Molecular Switches, Regulating the Choice between Growth Arrest and Apoptosis Induced by Galectin-8

Galectin-1 as a potential cancer target

Galectin-1 Interacts with the α5β1 Fibronectin Receptor to Restrict Carcinoma Cell Growth via Induction of p21 and p27

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