+ Site Statistics
+ Search Articles
+ PDF Full Text Service
How our service works
Request PDF Full Text
+ Follow Us
Follow on Facebook
Follow on Twitter
Follow on LinkedIn
+ Subscribe to Site Feeds
Most Shared
PDF Full Text
+ Translate
+ Recently Requested

Expression of connective tissue growth factor, a biomarker in senescence of human diploid fibroblasts, is up-regulated by a transforming growth factor-beta-mediated signaling pathway



Expression of connective tissue growth factor, a biomarker in senescence of human diploid fibroblasts, is up-regulated by a transforming growth factor-beta-mediated signaling pathway



Biochemical and Biophysical Research Communications 318(4): 819-825



Molecular changes associated with cellular senescence in human diploid fibroblasts (HDF), IMR-90, were analyzed by two-dimensional differential proteome analysis. A high percentage of replicative senescent cells were positive for senescence-associated beta-galactosidase activity, and displayed elevated levels of p21 and p53 proteins. Comparison of early population doubling level (PDL) versus replicative senescent cells among the 1000 spots resolved on gels revealed that the signal intensities of six spots were increased fivefold, whereas those of four spots were decreased. Proteome analysis data demonstrated that connective tissue growth factor (CTGF) is an age-associated protein. Up-regulation of CTGF expression in senescent cells was further confirmed by Western blotting and RT-PCR. We postulate that CTGF expression is controlled, in part, by transforming growth factor-beta (TGF-beta), in view of the high levels of TGF-beta isoforms as well as type I and II receptors detected only in late PDL of HDF cells. To verify this hypothesis, we stimulated early PDL cells with TGF-beta1 as well as stress inducing agents such as hydrogen peroxide. As expected, CTGF expression and Smad protein phosphorylation were dramatically increased up to observed levels in normal replicative senescent cells. In vivo experiments disclosed that CTGF, pSmad, and p53 were constitutively expressed at basal levels in up to 18-month-old rat liver, and expression was significantly up-regulated in 24-month-old rat tissue. However, expression patterns were not altered at all periods examined in livers of caloric-restricted rats. In view of both in vitro and in vivo data, we propose that the TGF-beta/Smad pathway functions in the induction of CTGF, a novel biomarker protein of cellular senescence in human fibroblasts.

Please choose payment method:






(PDF emailed within 0-6 h: $19.90)

Accession: 012074221

Download citation: RISBibTeXText

PMID: 15147944

DOI: 10.1016/j.bbrc.2004.04.108


Related references

Expression of connective tissue growth factor, a biomarker in senescence of human diploid fibroblasts, is up-regulated by a transforming growth factor-$beta;-mediated signaling pathway. Biochemical and Biophysical Research Communications 318(4): 819-825, 2004

Smad3 and extracellular signal-regulated kinase 1/2 coordinately mediate transforming growth factor-beta-induced expression of connective tissue growth factor in human fibroblasts. Journal of Investigative Dermatology 124(6): 1162-1169, 2005

Signaling events required for transforming growth factor-beta stimulation of connective tissue growth factor expression by cultured human lung fibroblasts. Archives of Biochemistry and Biophysics 395(1): 103-112, 2001

Transforming growth factor beta induces anchorage-independent growth of NRK fibroblasts via a connective tissue growth factor-dependent signaling pathway. Cell Growth and Differentiation 8(1): 61-68, 1997

Transforming growth factor beta 1 modulates connective tissue growth factor expression via Smad2 signaling pathway in podocyte in vitro. Zhonghua Yi Xue Za Zhi 84(7): 574-577, 2004

Kahweol decreases hepatic fibrosis by inhibiting the expression of connective tissue growth factor via the transforming growth factor-beta signaling pathway. Oncotarget 8(50): 87086-87094, 2017

Epidermal growth factor up-regulates expression of transforming growth factor beta receptor type II in human dermal fibroblasts by phosphoinositide 3-kinase/Akt signaling pathway: Resistance to epidermal growth factor stimulation in scleroderma fibroblasts. Arthritis and Rheumatism 48(6): 1652-1666, 2003

To transdifferentiate human hypertrophic scar fibroblasts induced by connective tissue growth factor mediated transforming growth factor-beta 1 in vitro. Zhonghua Shao Shang Za Zhi 25(1): 49-52, 2009

Expression of connective tissue growth factor and low density lipoprotein receptor related protein induced by transforming growth factor beta 1 in human pulmonary fibroblasts-1. Beijing Da Xue Xue Bao. Yi Xue Ban 38(5): 506-509, 2006

Blockade of endogenous transforming growth factor beta signaling prevents up-regulated collagen synthesis in scleroderma fibroblasts: association with increased expression of transforming growth factor beta receptors. Arthritis and Rheumatism 44(2): 474-480, 2001

Expression and regulation of connective tissue growth factor by transforming growth factor beta and tumour necrosis factor alpha in fibroblasts isolated from strictures in patients with Crohn's disease. British Journal of Surgery 93(10): 1290-1296, 2006

Connective tissue growth factor is a Smad2 regulated amplifier of transforming growth factor beta actions in hepatocytes--but without modulating bone morphogenetic protein 7 signaling. Hepatology 49(6): 2021-2030, 2009

Hypertrophic scar fibroblasts have increased connective tissue growth factor expression after transforming growth factor-beta stimulation. Plastic and Reconstructive Surgery 116(5): 1387-90; Discussion 1391-2, 2005

Advanced glycation end-products induce connective tissue growth factor-mediated renal fibrosis predominantly through transforming growth factor beta-independent pathway. American Journal of Pathology 165(6): 2033-2043, 2004

Connective tissue growth factor expression and induction by transforming growth factor-beta is abrogated by simvastatin via a Rho signaling mechanism. American Journal of Physiology. Lung Cellular and Molecular Physiology 287(6): L1323-L1332, 2004