Direct activation of telomerase by GH via phosphatidylinositol 3′-kinase

Abstract

Telomerase is a ribonucleoprotein DNA polymerase that has been associated with cell proliferation, cell survival and apoptosis inhibition. Telomerase is regulated by specific growth factors, cytokines and hormones. The present study examines the effect of GH on telomerase activity and identifies the signal transduction pathway involved in this process in Chinese hamster ovary (CHO)4 cells, which express rat GH receptor cDNA. Telomeric repeat amplification protocol assays demonstrated that treating CHO4 cells with increasingly high doses of GH up-regulated telomerase activity with the maximum activation at 24 h. Similarly, GH activated telomerase in another cell system, primary cultures of rat hepatocytes. The telomerase activation in CHO4 cells was produced with an increase in hamster telomerase catalytic subunit (hamTERT) mRNA expression. The telomerase activity induced by GH was specifically blocked by the phosphatidylinositol 3 -kinase (PI3-K) inhibitor, LY294002, but not by the MAP kinase kinase inhibitor, PD98059. These findings suggest that GH could activate telomerase through the direct activation of TERT transcription, as well as through the PI3-K signalling pathway.

Telomerase activity promotes osteoblast differentiation by modulating IGF-signaling pathway

“…We observed up-regulation of IGF-related genes including AKT phosphorylation in response to increased telomerase activity in hMSC suggesting the involvement of IGF/AKT signaling pathway in mediating the telomerase functional effects. The association between telomerase activity and PI3 K/AKT signaling pathway has previously been reported in a number of cellular models including growth hormone dependent telomerase activation via PI3 K signaling in Chinese hamster ovary cells (Gomez-Garcia et al 2005 ). Also, transcriptional activation of hTERT in human T cell leukemia—lymphoma virus-1 infected cells was mediated by PI3K (Bellon and Nicot 2008 ) and PI3K/AKT-dependent activation of hTERT was reported to be accomplished by ectopic expression of EGFR in oral squamous epithelial cells (Heeg et al 2011 ).…”

The telomerase activator TA‐65 elongates short telomeres and increases health span of adult/old mice without increasing cancer incidence

“…Whether or not TA-65 could regulate post-transcriptionally the levels of telomerase in the liver or other tissues has not been assessed here or elsewhere, although this is improbable in the case of mouse telomerase since some mTERT post-translational modifications such as phosphorylation is mediated through the AKT pathway, which seems not to be influenced by TA-65 (Kang et al . 1999; Gomez-Garcia et al . 2005; Fauce et al .…”

The oncogenic potential of growth hormone

“…The latter two are required for oncogenic transformation [102]. As autocrine hGH has also been demonstrated to upregulate telomerase activity ( [105], Emerald, unpublished), it is likely that autocrine hGH will also participate in the process of cell immortalisation. This raises the intriguing possibility that autocrine hGH may be sufficient to both immortalise and oncogenically transform the human mammary epithelial cell.…”