Synchronous Activation of ERK and Phosphatidylinositol 3-Kinase Pathways Is Required for Collagen and Extracellular Matrix Production in Keloids

Lim, Ivor J.; Phan, Toan Thang; Tan, Edwin T.; Nguyen, T.T.T.; Tran, Elizabeth; Longaker, Michael T.; Song, Colin; Lee, Seng-Teik; Huynh, H.

doi:10.1074/jbc.m305759200

Cited by 71 publications

(69 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Overexpression of constitutively active Akt or the PI3K p110α subunit in embryoid bodies resulted in massive collagen 4A1 and laminin accumulation [6]. Abnormal production of collagens 1, 2, 3 and laminin, as well as extracellular fibronectin assembly by keloid fibroblasts were blocked by LY294002 [31]; this role in fibronectin matrix assembly has also been seen in other cell types [32]. In hepatic stellate cells, basal collagen IA1 mRNA levels were decreased by LY294002 [7].…”

Section: Discussionmentioning

confidence: 93%

Collagen I induction by high glucose levels is mediated by epidermal growth factor receptor and phosphoinositide 3-kinase/Akt signalling in mesangial cells

Peng

Zhang

et al. 2007

Diabetologia

View full text Add to dashboard Cite

Aims/hypothesis Glomerular matrix accumulation is a hallmark of diabetic nephropathy. Recent data have linked the serine/threonine kinase protein kinase B (Akt) to matrix modulation. Here, we studied its role in high glucoseinduced collagen elaboration by mesangial cells. Methods Primary rat mesangial cells were treated with high glucose levels (30 mmol/l) or mannitol as osmotic control. Western blots, northern blots, ELISA and immunohistochemistry were used for assessment. Diabetes was induced in rats by streptozotocin.

show abstract

Section: Discussionmentioning

confidence: 93%

Collagen I induction by high glucose levels is mediated by epidermal growth factor receptor and phosphoinositide 3-kinase/Akt signalling in mesangial cells

Peng

Zhang

et al. 2007

Diabetologia

View full text Add to dashboard Cite

show abstract

“…Collagen and laminin secretion by keloid fibroblasts was also shown to be dependent on PI3K (20), as was fibronectin production by MC in response to TGF-␤ (37). Accumulation of matrix components is the sine qua non of progressive sclerotic glomerular injury in vivo.…”

Section: Discussionmentioning

confidence: 99%

“…PI3K was shown to be important in basal production of collagen 1A1 transcript levels in hepatic stellate cells and human lung fibroblasts (18,19). Abnormal production of collagen and laminin, as well as extracellular fibronectin assembly, by keloid fibroblasts was dependent on PI3K (20), and this role in fibronectin matrix assembly has also been seen in other cell types (21). The PI3K/ Akt pathway has also been shown to mediate TGF-␤-induced collagen 1A1 and 1A2 upregulation in lung fibroblasts and MC (19,22).…”

mentioning

confidence: 98%

Akt Mediates Mechanical Strain-Induced Collagen Production by Mesangial Cells

Krepinsky¹,

Li²,

Chang³

et al. 2005

Journal of the American Society of Nephrology

View full text Add to dashboard Cite

Increased glomerular hydrostatic pressure is an important determinant of glomerulosclerosis and can be modeled by in vitro exposure of mesangial cells to cyclic mechanical strain. Stretched mesangial cells increase extracellular matrix protein production, the hallmark of glomerulosclerosis. Recent data indicate that the serine/threonine kinase Akt may be involved in matrix modulation. Thus, Akt activation and matrix synthesis in stretched mesangial cells were studied. Exposure of mesangial cells to 1 Hz cyclic strain led to prompt Akt activation, which was biphasic to 24 h. Activation was dependent on signaling through phosphatidylinositol-3-kinase and required EGF receptor transactivation. Inhibition of signaling through the PDGF receptor, Src kinase, or cytoskeletal disruption failed to prevent strain-induced Akt activation. Collagen type 1A1 transcript expression, promoter activation, and protein secretion were increased by stretch at 24 h and were dependent on phosphatidylinositol-3 kinase. Overexpression of dominant-negative Akt inhibited strain-induced collagen 1A1 production. Conversely, overexpression of constitutively active Akt led to increased collagen 1A1 upregulation and secretion. Finally, Akt activation was observed in the glomeruli of remnant rat kidneys, a model marked by increased intraglomerular pressure. The authors conclude that mechanical strain induces Akt activation in mesangial cells through a mechanism requiring phosphatidylinositol-3-kinase and EGF receptor transactivation. Type 1 collagen production is dependent on Akt and can be induced by Akt overexpression. Akt activation is observed in remnant kidneys in vivo. Thus, the role of Akt in progression of chronic hemodynamic glomerular disease is worthy of further exploration.

show abstract

“…4, Akt and p-Akt were decreased after CSE exposure, and MSC-CM resulted in restoration of the levels of both. Because the PI3K/Akt pathway is known to act as a survival signaling hub (30) and to be involved in ECM protein expression (25,26), we investigated the contribution of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway to the effects of MSC-CM. LY294002, a PI3K inhibitor, inhibited Akt phosphorylation induced by MSC-CM (Fig.…”

Section: Cse Induces Apoptotic Death In Lung Fibroblastsmentioning

confidence: 99%

Mesenchymal stem cell-conditioned media recovers lung fibroblasts from cigarette smoke-induced damage

Kim

Lee

Kim

et al. 2012

American Journal of Physiology-Lung Cellular and Molecular Phys

View full text Add to dashboard Cite

Lee Y-S. Mesenchymal stem cell-conditioned media recovers lung fibroblasts from cigarette smoke-induced damage. Am J Physiol Lung Cell Mol Physiol 302: L891-L908, 2012. First published February 3, 2012 doi:10.1152/ajplung.00288.2011.-Cigarette smoking causes apoptotic death, senescence, and impairment of repair functions in lung fibroblasts, which maintain the integrity of alveolar structure by producing extracellular matrix (ECM) proteins. Therefore, recovery of lung fibroblasts from cigarette smoke-induced damage may be crucial in regeneration of emphysematous lung resulting from degradation of ECM proteins and subsequent loss of alveolar cells. Recently, we reported that bone marrow-derived mesenchymal stem cell-conditioned media (MSC-CM) led to angiogenesis and regeneration of lung damaged by cigarette smoke. In this study, to further investigate reparative mechanisms for MSC-CM-mediated lung repair, we attempted to determine whether MSC-CM can recover lung fibroblasts from cigarette smoke-induced damage. In lung fibroblasts exposed to cigarette smoke extract (CSE), MSC-CM, not only inhibited apoptotic death, but also induced cell proliferation and reversed CSE-induced changes in the levels of caspase-3, p53, p21, p27, Akt, and p-Akt. MSC-CM also restored expression of ECM proteins and collagen gel contraction while suppressing CSE-induced expression of cyclooxygenase-2 and microsomal PGE 2 synthase-2. The CSE-opposing effects of MSC-CM on cell fate, expression of ECM proteins, and collagen gel contraction were partially inhibited by LY294002, a phosphatidylinositol 3-kinase (PI3K) inhibitor. In rats, MSC-CM administration also resulted in elevation of p-Akt and restored proliferation of lung fibroblasts, which was suppressed by exposure to cigarette smoke. Taken together, these data suggest that MSC-CM may recover lung fibroblasts from cigarette smoke-induced damage, possibly through inhibition of apoptosis, induction of proliferation, and restoration of lung fibroblast repair function, which are mediated in part by the PI3K/Akt pathway. cigarette smoking; chronic obstructive pulmonary disease; emphysema CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD), a leading cause of death worldwide, is most often caused by cigarette smoking. COPD is characterized by expiratory airflow limitation that is not fully reversible, accompanying inflammation, and emphysematous destruction of the lung (39). Irrespective of the high incidence and mortality rates for COPD, most current therapies for this disease are supportive, and regenerative therapies to cure emphysema are not available.As a pathophysiological mechanism, proteolytic degradation of extracellular matrix (ECM) by protease activities overwhelming antiprotease activities has long been suspected to be responsible for the emphysematous change seen in patients with COPD (45). Lung fibroblasts are considered crucial for maintenance of the integrity of alveolar structure by producing ECM proteins, including collagen, elastin, and fibronectin, which are required for attach...

show abstract

Synchronous Activation of ERK and Phosphatidylinositol 3-Kinase Pathways Is Required for Collagen and Extracellular Matrix Production in Keloids

Cited by 71 publications

References 32 publications

Collagen I induction by high glucose levels is mediated by epidermal growth factor receptor and phosphoinositide 3-kinase/Akt signalling in mesangial cells

Collagen I induction by high glucose levels is mediated by epidermal growth factor receptor and phosphoinositide 3-kinase/Akt signalling in mesangial cells

Akt Mediates Mechanical Strain-Induced Collagen Production by Mesangial Cells

Mesenchymal stem cell-conditioned media recovers lung fibroblasts from cigarette smoke-induced damage

Contact Info

Product

Resources

About