Expression of insulin-like growth factor-1 and insulin-like growth factor-1 receptors in EL4 lymphoma cells overexpressing growth hormone

Weigent, Douglas A.; Arnold, Robyn

doi:10.1016/j.cellimm.2005.04.016

Cited by 20 publications

(17 citation statements)

References 70 publications

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“…These actions are likely mediated through autocrine or paracrine mechanisms, as DNA fragmentation is increased when GH expression is prevented by GH antisense oligonucleotides [255]. The anti-apoptotic action of GH overexpression is mediated through increased IGF-1 production and IGF-1 receptors, as it is blocked by antibodies to IGF-1 or its receptor [256].…”

Section: Gh In Cancersmentioning

confidence: 97%

Extrapituitary growth hormone

Harvey

2010

Endocr

108

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Pituitary somatotrophs secrete growth hormone (GH) into the bloodstream, to act as a hormone at receptor sites in most, if not all, tissues. These endocrine actions of circulating GH are abolished after pituitary ablation or hypophysectomy, indicating its pituitary source. GH gene expression is, however, not confined to the pituitary gland, as it occurs in neural, immune, reproductive, alimentary, and respiratory tissues and in the integumentary, muscular, skeletal, and cardiovascular systems, in which GH may act locally rather than as an endocrine. These actions are likely to be involved in the proliferation and differentiation of cells and tissues prior to the ontogeny of the pituitary gland. They are also likely to complement the endocrine actions of GH and are likely to maintain them after pituitary senescence and the somatopause. Autocrine or paracrine actions of GH are, however, sometimes mediated through different signaling mechanisms to those mediating its endocrine actions and these may promote oncogenesis. Extrapituitary GH may thus be of physiological and pathophysiological significance.

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Section: Gh In Cancersmentioning

confidence: 97%

Extrapituitary growth hormone

Harvey

2010

Endocr

108

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“…Some studies, however, have shown that IGF-IR is over-expressed in some types of lymphoma cells [22, 23, 175, 176]. Studies from our lab supported a role for IGF-IR in nucleophosmin-ALK-expressing (NPM-ALK + ) T-cell lymphoma [22].…”

Section: Role Of Igf-ir Signaling In Hematological Malignanciesmentioning

confidence: 70%

“…As mentioned previously, GH regulates the secretion of IGF-I by the liver, although IGF-I concentrations can arise independently of GH. The EL4 lymphoma model may demonstrate a potential method of upregulation of IGF-IR via GH [175]. …”

Section: Role Of Igf-ir Signaling In Hematological Malignanciesmentioning

confidence: 99%

Type I insulin-like growth factor receptor signaling in hematological malignancies

et al. 2016

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The insulin-like growth factor (IGF) signaling system plays key roles in the establishment and progression of different types of cancer. In agreement with this idea, substantial evidence has shown that the type I IGF receptor (IGF-IR) and its primary ligand IGF-I are important for maintaining the survival of malignant cells of hematopoietic origin. In this review, we discuss current understanding of the role of IGF-IR signaling in cancer with a focus on the hematological neoplasms. We also address the emergence of IGF-IR as a potential therapeutic target for the treatment of different types of cancer including plasma cell myeloma, leukemia, and lymphoma.

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“…Both GH and GHR are expressed in immune cells and are implicated in the development of leukemia and lymphoma (Hooghe et al, 1998) along with IGF-1 and its receptor (Weigent & Arnold, 2005). The overexpression of GH and GHR in lymphoma cells have been shown to have anti-apoptotic effects (besides increasing IGF-1) by decreasing the production of superoxide and associated expression of bax, Bad and caspases 3,8 and 9 (Arnold & Weigent, 2003).…”

Section: Mammary and Endometrial Cancermentioning

confidence: 99%

“…Autocrine GH is thought to enhance the in vitro oncogenic potential of endometrial carcinoma and colorectal cells while its forced expression in immortalised endometrial carcinoma and breast cancer cell lines increased their cell number through enhanced cell cycle progression and decreased apoptotic cell death while promoting anchorage-independent growth and increased cell migration and invasion (Jenkins & Bustin, 2004;Pandey et al, 2008;. Both GH and GHR are expressed in immune cells and are implicated in the development of leukemia and lymphoma (Hooghe et al, 1998) along with IGF-1 and its receptor (Weigent & Arnold, 2005). The overexpression of GH and GHR in lymphoma cells have been shown to have anti-apoptotic effects (besides increasing IGF-1)…”

Section: Autocrine Mode Of Gh Signallingmentioning

confidence: 99%

The growth hormone receptor mediated oncogenesis

Chhabra¹

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Growth hormone (GH) is a major regulator of postnatal growth, cellular proliferation and differentiation, as well as of metabolism. All actions of GH are mediated via its cognate Growth Hormone Receptor (GHR). It is now clear that the role of GH extends well beyond the conventional notions of longitudinal growth and childhood development. A substantial body of evidence supports a role for the GH/IGF-1 axis in cancer incidence and progression in animals and humans and because of widespread clinical application of GH, there has been considerable interest in the mechanism of activation of its receptor. It was originally thought that GH initiated its actions by sequentially binding two GHR monomers, resulting in receptor dimerisation and initiation of intracellular signalling cascades, including Jak/STAT and MAPK pathways. However, recent evidence by our group and others has indicated that the GHR is constitutively dimerised, and that dimerisation alone is not sufficient for GHR activation.To this end the main objective of this thesis was to evaluate the role of GH-mediated signalling via its GHR in mediating oncogenesis. We have taken a multi-disciplinary approach by first determining how the GHR is activated via its transmembrane domain (TMD) and the nature of its interaction with Src family of tyrosine kinase (Lyn). We have determined the basis of the contrasting actions of autocrine GH from independent publications and sought to evaluate the effect of various constitutively active GHR constructs in cancer promotion in vitro and in vivo by establishing a tissue-specific delivery system (TVA system) for introducing multiple genes in a spatial and temporally controlled manner. We have provided the molecular basis of increased cancer susceptibility of the first reported GHR variant from two independent epidemiological studies. Finally, we have evaluated cancer resistance and anti-aging pathways in various GHR knockin and knockout mice models.In order to determine the role of GHR transmembrane domain (TMD) and upper juxtamembrane domain (JMD) in signalling, cysteine-scanning mutagenesis was employed with truncated and full length receptors in a thiol-free background. Using these GHR constructs and sequentially substituting residues along the GHR JMD and TMD with cysteine we observed a ligandindependent spontaneous dimerisation pattern of upper JMD and TMD residues with evidence for a 'tilt and twist' movement for this region of GHR during activation. By using Cu-o-phenanthroline we were able to show that GHR activation could occur following disulfide bond formation at the upper TMD boundary resulting in constitutive activation. Finally we were able to conclude that GHR activation requires the JMD residues to come in close proximity which results in separation of iii the lower TMD residues and activation. Another outcome of this study was the generation of the first full-length constitutively active receptor.GHR has been shown to activate numerous pathways and one such pathway involves Src Family Kinase (SFK),...

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Expression of insulin-like growth factor-1 and insulin-like growth factor-1 receptors in EL4 lymphoma cells overexpressing growth hormone

Cited by 20 publications

References 70 publications

Extrapituitary growth hormone

Extrapituitary growth hormone

Type I insulin-like growth factor receptor signaling in hematological malignancies

The growth hormone receptor mediated oncogenesis

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