The ras oncogenes

Marshall, Christopher J.

doi:10.1242/jcs.1988.supplement_10.12

Cited by 23 publications

(14 citation statements)

References 58 publications

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“…Already since the 1980ies it is known that mutant Ras proteins occur in a considerable number of human cancer patients [281,282]. They do therefore not depend anymore on activation through the Sos proteins.…”

Section: Sosmentioning

confidence: 99%

Potential Disease Targets for Drugs that Disrupt Protein - Protein Interactions of Grb2 and Crk Family Adaptors

Feller¹,

Lewitzky²

2006

CPD

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This review summarises some of the knowledge we have about Crk and Grb2 family adaptor protein signalling in health and disease and outlines the current status and the challenges still remaining in the development of efficient and selective inhibitors of their protein -protein interactions. It also highlights briefly some recent successes and problems of inhibitors for proteins that functionally interact with Crk and Grb2 family adaptors, as well as opportunities, which may arise from combination therapies. Grb2 and Crk family adaptors regulate signalling pathways linked to human diseases. They are mainly composed of Src homology 2 (SH2) and Src homology 3 (SH3) domains, which serve as docking sites for signalling proteins, including various receptors, cytoplasmic kinases and GTPase regulators. Considerable insight into the biological functions and mechanisms of action of small SH2/SH3 domain adaptors has been gained in the last years from experimental approaches as diverse as targeted gene disruption and structural studies at the atomic level. This has already indicated several strategies to utilise SH2 and SH3 domain interaction inhibitors in human disease therapy. Additional molecular targets for Crk and Grb2 domain interaction blockers are expected to surface as further protein-protein interactions are discovered. Examples include newly found DOCK family proteins (DOCK3, DOCK4, and DOCK5) which are known or suspected effectors of Crk proteins and the interaction of Grb2 with the cell cycle regulator p27Kip1.

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Section: Sosmentioning

confidence: 99%

Potential Disease Targets for Drugs that Disrupt Protein - Protein Interactions of Grb2 and Crk Family Adaptors

Feller¹,

Lewitzky²

2006

CPD

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“…The Ras/Raf/mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) cascade regulates proliferation, differentiation, survival, motility, and tissue formation (7-16). Mutated forms of Ras are found in 30% of human cancers (9-11) including RMS (12) and mutations produce proteins that remain locked in a constitutively active state, thereby relaying uncontrolled signals (13). The Ras-MAPK pathway when constitutively activated mediates resistance to ionizing radiation (14) through EGF induction and EGF-receptor mediated activation of prosurvival PI3K-AKT pathway which in turn activates DNA protein kinase catalytic subunit (DNA-PKcs) (15).…”

Section: Introductionmentioning

confidence: 99%

MEK/ERK Inhibitor U0126 Increases the Radiosensitivity of Rhabdomyosarcoma Cells In vitro and In vivo by Downregulating Growth and DNA Repair Signals

Marampon

Gravina

Rocco

et al. 2011

Molecular Cancer Therapeutics

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Multimodal treatment has improved the outcome of many solid tumors, and in some cases the use of radiosensitizers has significantly contributed to this gain. Activation of the extracellular signaling kinase pathway (MEK/ERK) generally results in stimulation of cell growth and confers a survival advantage playing the major role in human cancer. The potential involvement of this pathway in cellular radiosensitivity remains unclear. We previously reported that the disruption of c-Myc through MEK/ERK inhibition blocks the expression of the transformed phenotype; affects in vitro and in vivo growth and angiogenic signaling; and induces myogenic differentiation in the embryonal rhabdomyosarcoma (ERMS) cell lines (RD). This study was designed to examine whether the ERK pathway affects intrinsic radiosensitivity of rhabdomyosarcoma cancer cells. Exponentially growing human ERMS, RD, xenograft-derived RD-M1, and TE671 cell lines were used. The specific MEK/ERK inhibitor, U0126, reduced the clonogenic potential of the three cell lines, and was affected by radiation. U0126 inhibited phospho-active ERK1/2 and reduced DNA protein kinase catalytic subunit (DNA-PKcs) suggesting that ERKs and DNA-PKcs cooperate in radioprotection of rhabdomyosarcoma cells. The TE671 cell line xenotransplanted in mice showed a reduction in tumor mass and increase in the time of tumor progression with U0126 treatment associated with reduced DNA-PKcs, an effect enhanced by radiotherapy. Thus, our results show that MEK/ERK inhibition enhances radiosensitivity of rhabdomyosarcoma cells suggesting a rational approach in combination with radiotherapy.

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“…Over the past decade, the Epo-stimulated intracellular signalling pathways that direct these responses have largely been elucidated, for example, JAK/STAT and ras/MAP kinase cascades (Ihle, 1995;Klingmuller, 1997;Constantinescu et al, 1999;Tilbrook and Klinken, 1999). Significantly, abnormalities in the JAK/STAT and ras pathway have been associated with cancer induction (Marshall, 1988;Waldmann and Rabes, 1996;Bromberg et al, 1999;Lacronique et al, 1997).…”

Section: Introductionmentioning

confidence: 99%

Differential regulation of SOCS genes in normal and transformed erythroid cells

et al. 2003

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The SOCS family of genes are negative regulators of cytokine signalling with SOCS-1 displaying tumor suppressor activity. SOCS-1, CIS and SOCS-3 have been implicated in the regulation of red blood cell production. In this study, a detailed examination was conducted on the expression patterns of these three SOCS family members in normal erythroid progenitors and a panel of erythroleukemic cell lines. Unexpectedly, differences in SOCS gene expression were observed during maturation of normal red cell progenitors, viz changes to CIS were inversely related to the alterations of SOCS-1 and SOCS-3. Similarly, these SOCS genes were differentially expressed in transformed erythoid cellserythroleukemic cells immortalized at an immature stage of differentiation expressed SOCS-1 and SOCS-3 mRNA constitutively, whereas in more mature cell lines SOCS-1 and CIS were induced only after exposure to erythropoietin (Epo). Significantly, when ectopic expression of the tyrosine kinase Lyn was used to promote differentiation of immature cell lines, constitutive expression of SOCS-1 and SOCS-3 was completely suppressed. Modulation of intracellular signalling via mutated Epo receptors in mature erythroleukemic lines also highlighted different responses by the three SOCS family members. Close scrutiny of SOCS-1 revealed that, despite large increases in mRNA levels, the activity of the promoter did not alter after erythropoietin stimulation; in addition, erythroid cells from SOCS-1À/À mice displayed increased sensitivity to Epo. These observations indicate complex, stagespecific regulation of SOCS genes during normal erythroid maturation and in erythroleukemic cells.

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The ras oncogenes

Cited by 23 publications

References 58 publications

Potential Disease Targets for Drugs that Disrupt Protein - Protein Interactions of Grb2 and Crk Family Adaptors

Potential Disease Targets for Drugs that Disrupt Protein - Protein Interactions of Grb2 and Crk Family Adaptors

MEK/ERK Inhibitor U0126 Increases the Radiosensitivity of Rhabdomyosarcoma Cells In vitro and In vivo by Downregulating Growth and DNA Repair Signals

Differential regulation of SOCS genes in normal and transformed erythroid cells

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