Distinct functions of H‐Ras and K‐Ras in proliferation and survival of primary hepatocytes due to selective activation of ERK and PI3K

Rosseland, Carola M.; Wierød, Lene; Flinder, Liv Ingrid; Oksvold, Morten P.; Skarpen, Ellen; Huitfeldt, Henrik S.

doi:10.1002/jcp.21367

Cited by 23 publications

(28 citation statements)

References 43 publications

(47 reference statements)

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“…These results are consistent with early reports that a Gal-3 mutant which was not phosphorylated (S6A) and was not exported from the nucleus did not protect BT cancer cell lines from drug-induced apoptosis [32], [33]. It is possible that CK1 phosphorylation of Gal-3 might modulate the anti-apoptotic effects of K-Ras [34] and Gal-3 [33], [35].…”

Section: Discussionsupporting

confidence: 92%

Galectin-3 Mediates Cross-Talk between K-Ras and Let-7c Tumor Suppressor microRNA

et al. 2011

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BackgroundGalectin-3 (Gal-3) and active (GTP-bound) K-Ras contribute to the malignant phenotype of many human tumors by increasing the rate of cell proliferation, survival, and migration. These Gal-3-mediated effects result from a selective binding to K-Ras.GTP, causing increased nanoclustering in the cell membrane and leading to robust Ras signaling. Regulation of the interactions between Gal-3 and active K-Ras is not fully understood.Methods and FindingsTo gain a better understanding of what regulates the critical interactions between these two proteins, we examined the role of Gal-3 in the regulation of K-Ras by using Gal-3-knockout mouse embryonic-fibroblasts (Gal-3-/- MEFs) and/or Gal-3/Gal-1 double-knockout MEFs. We found that knockout of Gal-3 induced strong downregulation (∼60%) of K-Ras and K-Ras.GTP. The downregulation was somewhat more marked in the double-knockout MEFs, in which we also detected robust inhibition(∼50%) of ERK and Akt activation. These additional effects are probably attributable to inhibition of the weak interactions of K-Ras.GTP with Gal-1. Re-expression of Gal-3 reversed the phenotype of the Gal-3-/- MEFs and dramatically reduced the disappearance of K-Ras in the presence of cycloheximide to the levels seen in wild-type MEFs. Furthermore, phosphorylation of Gal-3 by casein kinase-1 (CK-1) induced translocation of Gal-3 from the nucleus to the cytoplasm and the plasma membrane, leading to K-Ras stabilization accompanied by downregulation of the tumor suppressor miRNA let-7c, known to negatively control K-Ras transcription.ConclusionsOur results suggest a novel cross-talk between Gal-3-mediated downregulation of let 7c microRNA (which in turn negatively regulates K-Ras transcription) and elucidates the association among Gal-3 let-7c and K-Ras transcription/translation, cellular compartmentalization and activity.

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Section: Discussionsupporting

confidence: 92%

Galectin-3 Mediates Cross-Talk between K-Ras and Let-7c Tumor Suppressor microRNA

et al. 2011

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“…Finally, we demonstrated that the Hras G12V -induced growth phenotype is almost fully reversible via apoptosis, indicating that maintenance of increased liver weight requires the continuous presence of mutant ras, and consistent with the reported association of mutant ras expression with hepatocyte survival (28). Loss of Hras G12V anti-apoptotic activity promotes liver mass normalization via hepatocyte death.…”

Section: Discussionsupporting

confidence: 90%

Mutant Hras^G12V and Kras^G12D have overlapping, but non‐identical effects on hepatocyte growth and transformation frequency in transgenic mice

Figueiredo

Stein

Jochem

et al. 2012

Liver International

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Background Mouse hepatocarcinogenesis is associated with mutations in Hras but infrequently in Kras. The effect on carcinogenesis of developmental age at the time of ras mutation is unknown. Aim We sought to compare quantitatively the effects of expressing mutant H- or Kras genes in fetal versus adult mouse liver. Methods We established an inducible system of gene expression in mouse liver to define disease pathogenesis associated with activation of oncogene expression. Results Diffuse expression of either oncogene in fetal or adult hepatocytes caused hepatomegaly. For mutant HrasG12V, this phenotype was almost fully reversible and accompanied by apoptosis, indicating that maintenance of hepatomegaly requires continuous HrasG12V expression. We also examined the effect of ras expression on growth of transplanted hepatocytes in an in vivo system that allows us to quantify hepatocyte growth effects in both permissive and restrictive hepatic growth environments. Mutant KrasG12D had no effect on hepatocyte growth in this sysstem. In contrast, HrasG12V induced increased hepatocyte focus growth in quiescent liver, the hallmark of a cell autonomous growth stimulus. HrasG12V also increased the fraction of donor hepatocyte foci that displayed extreme growth, a characteristic of preneoplastic lesions. Conclusions The primary effect of diffuse, whole-liver expression of either mutant ras gene in fetal or adult mouse liver is diffuse and progressive hepatic growth. HrasG12V mutation influences hepatocarcinogenesis by conferring cell autonomous growth potential upon foci of expressing cells and by increasing the risk of neoplastic progression. KrasG12D does not share these latter carcinogenic effects in mouse liver.

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“…In the present study, the PI3K pathway was differentially regulated by alcohol treatment in mutant mice with bidirectional perturbation of K-ras function as determined by GSEA analysis. The insulin/PI3K and the NF-κB pathways are involved in K-ras signaling (Guerra et al, 2003; Rosseland et al, 2008; Wang et al, 1999) and neural plasticity (Izzo et al, 2002; Russo et al, 2009). Polymorphisms of PI3K p85 α (Desrivieres et al, 2008) and NF-κB1 (Edenberg et al, 2008) affect the risk for alcoholism in humans and adaptations of the NF-κB system have been observed in human alcoholics (Okvist et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

Genome-wide gene expression analysis identifies K-ras as a regulator of alcohol intake

et al. 2010

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Adaptations in the anterior cingulate cortex (ACC) have been implicated in alcohol and drug addiction. To identify genes that may contribute to excessive drinking, here we performed microarray analyses in laser microdissected rat ACC after a single or repeated administration of an intoxicating dose of alcohol (3g/kg). Expression of the small G protein K-ras was reduced following both single and repeated alcohol administration. We also observed that voluntary alcohol intake in K-ras heterozygous null mice (K-ras +/− ) did not increased after withdrawal from repeated cycles of intermittent ethanol vapor exposure, unlike in their wild-type littermates. To identify K-ras regulated pathways, we then profiled gene expression in the ACC of K-ras +/− , heterozygous null mice for the K-ras negative regulator Nf1 (Nf1 +/− ) and wild-type mice following repeated administration of an intoxicating dose of alcohol. Pathway analysis showed that alcohol differentially affected various pathways in a K-ras dependent manner -some of which previously shown to be regulated by alcohol -including the insulin/PI3K pathway, the NF-kB, the phosphodiesterases (PDEs) pathway, the Jak/Stat and the adipokine signaling pathways. Altogether, the data implicate K-ras-regulated pathways in the regulation of excessive alcohol drinking after a history of dependence.

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Distinct functions of H‐Ras and K‐Ras in proliferation and survival of primary hepatocytes due to selective activation of ERK and PI3K

Cited by 23 publications

References 43 publications

Galectin-3 Mediates Cross-Talk between K-Ras and Let-7c Tumor Suppressor microRNA

Galectin-3 Mediates Cross-Talk between K-Ras and Let-7c Tumor Suppressor microRNA

Mutant Hras^G12V and Kras^G12D have overlapping, but non‐identical effects on hepatocyte growth and transformation frequency in transgenic mice

Genome-wide gene expression analysis identifies K-ras as a regulator of alcohol intake

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Distinct functions of H‐Ras and K‐Ras in proliferation and survival of primary hepatocytes due to selective activation of ERK and PI3K

Cited by 23 publications

References 43 publications

Galectin-3 Mediates Cross-Talk between K-Ras and Let-7c Tumor Suppressor microRNA

Galectin-3 Mediates Cross-Talk between K-Ras and Let-7c Tumor Suppressor microRNA

Mutant HrasG12V and KrasG12D have overlapping, but non‐identical effects on hepatocyte growth and transformation frequency in transgenic mice

Genome-wide gene expression analysis identifies K-ras as a regulator of alcohol intake

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Mutant Hras^G12V and Kras^G12D have overlapping, but non‐identical effects on hepatocyte growth and transformation frequency in transgenic mice