Signal transduction via the growth hormone receptor

Self Cite

We herein demonstrate that autocrine human growth hormone production in human mammary carcinoma cells results in increased telomerase activity as a result of specific up-regulation of telomerase catalytic subunit (human telomerase reverse transcriptase (hTERT)) mRNA and protein. This increase in hTERT gene expression is not due to increased transcriptional activation of the hTERT promoter but is the result of increased stability of hTERT mRNA exerted by CU-rich cis-regulatory sequences present in the 3-untranslated region of TERT mRNA. Autocrine human growth hormone up-regulates two poly(C)-binding proteins, ␣CP1 and ␣CP2, which bind to these cis-regulatory elements and stabilize hTERT mRNA. We have therefore demonstrated that post-transcriptional modulation of the level of hTERT mRNA is one mechanism for regulation of cellular telomerase activity.Chromosomal ends consist of small DNA repeats that are not duplicated faithfully during replication resulting in loss of DNA during each replication. To faithfully replicate chromosomal ends, cells use a reverse transcriptase holoenzyme termed the telomerase complex (1). The template human telomerase RNA (hTR) 3 and the reverse transcriptase catalytic subunit (hTERT) are considered to be the major components of the human telomerase complex, because the expression of hTERT and hTR alone is able to restore the majority of telomerase activity (2). Telomerase activity is subject to stringent regulation and is regulated by multiple mechanisms such as hTERT mRNA transcription (3), splicing and maturation (4), protein phosphorylation and transport (5), and subcellular localization of each component of the telomerase complex (6). Telomerase activity is minimal in most somatic cells resulting in chromosome shortening after each proliferative cycle eventually resulting in crisis and cell death (7). However, telomerase activity is readily detected in 90% of all tumor cells (8), in all tissues during early development (9), and in tissues with continuous proliferation, such as the hematopoietic system or the epidermis (10, 11).mRNA turnover is one important mechanism by which gene expression is regulated (13). Specific interactions between sequences within the mRNA (cis-acting regulatory elements) and cellular RNA-binding proteins (trans-acting factors) regulate ribonuclease action and subsequent mRNA decay rates. The majority of these cis-acting elements are present in the 3Ј-untranslated region (3Ј-UTR) of the mRNA. cis-Regulatory elements such as AU-rich elements (12), Iron-responsive element (14), and CU-rich elements (15) within the 3Ј-UTR have been demonstrated to possess a role in mRNA stability. ␣-Globin mRNA poly(C)-rich segment-binding proteins (␣CPs), also referred to as poly(C)-binding proteins, and hnRNP K bind to CU-rich cis-regulatory elements (16). Two of the five members of poly(C)-binding proteins, ␣CP1 and ␣CP2, are highly homologous (16). Both ␣CP1 and ␣CP2 bind to pyrimidinerich elements in the 3Ј-UTR and stabilize a variety of mRNAs including ␣-globin and eryt...

Section: Resultsmentioning

confidence: 97%

αCP1 Mediates Stabilization of hTERT mRNA by Autocrine Human Growth Hormone

Emerald

Chen

Zhu

et al. 2007

Self Cite

“…GH binding to the dimeric GHR induces a rotation in the GHR tail (1,2) that subsequently leads to activation of Jak2 and, ultimately, to activation of signaling cascades via Stat5b, ERK, and MAP kinase pathways (reviewed in Ref. 3). Endocytosis and degradation of the GHR determine largely the sensitivity of cells for GH (4).…”

Section: Growth Hormone Receptor (Ghr)mentioning

confidence: 99%

Ubc13 and COOH Terminus of Hsp70-interacting Protein (CHIP) Are Required for Growth Hormone Receptor Endocytosis

Slotman

Almeida

Hassink

et al. 2012

Background:The scientific question that we address is how cytokine receptors organize their degradation. Results: CHIP and Ubc13 are required for GH receptor endocytosis, implicating Lys 63 -specific ubiquitination. Conclusion: This study shows how two ubiquitin ligases act in concert to allow receptor endocytosis. Significance: Understanding this mechanism enables drug design to control GH signaling in fighting cancer and cachexia.

“…GH exerts its biological effects by binding to its receptor (GHR), a member of the cytokine receptor superfamily (9); this results in receptor dimerization and tyrosine phosphorylation of an associated Janus kinase (JAK2). Activated JAK2 in turn phosphorylates the intracellular domain of the GHR, and the GHR-JAK2 complex provides docking sites for a variety of signaling molecules of the signal transducer and activator of transcription family (STAT) (9,10). GH activates mainly STAT5, and to a lesser degree, STAT3 and STAT1.…”

mentioning

confidence: 99%

CXCR4-mediated Suppressor of Cytokine Signaling Up-regulation Inactivates Growth Hormone Function

Garzón

Soriano

Rodrı́guez-Frade

et al. 2004

Coordinated action between cytokines and chemokines is required for effective endocrine and immune responses. Proteins of both families promote receptor oligomerization, activation of the Janus kinase (JAK)/ STAT pathway, and transcription of many genes, including the suppressor of cytokine signaling (SOCS) family. In this study, we show that chemokine-mediated SOCS1 and SOCS3 up-regulation modulates the signaling and function associated to a cytokine receptor, both in vitro and in vivo. The effect is mediated by SOCS binding to JAK2 and to the cytokine receptor, which blocks subsequent signaling events. The data reinforce the premise of cytokine-chemokine cross-talk, which helps contribute to modulating individual responses and in defining the functional plasticity of the immune system.