|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
 |
Article |
|---|
Top
References
|
|---|
Coordinated regulation of the mammalian cell cycle is essential for all biologic processes from conception, embryonic development, growth, differentiation, and eventual organism senescence. Not surprisingly, dysregulated cell cycle proliferation is a central feature of a wide spectrum of human diseases, including malignancies, fibroproliferative states, and degenerate disorders. Eukaryotic cell cycle traverse is tightly controlled by the coordinated expression of a class of conserved proteins known as cyclins, which rise and fall in abundance over the course of the mammalian cell cycle. The cyclins themselves lack catalytic activity, instead acting as essential scaffolding molecules for their associated cyclin-dependent kinase partners (cdks) (1). In turn, cdks phosphorylate histones, nuclear lamins, and other molecules essential for cellular proliferation. In mammalian cell cycle regulation, cyclin D1 and its catalytic partner, cdk4, are active in the G1 phase of the cell cycle and during transition to the DNA synthetic S phase of the cell cycle (2). Investigations have evaluated the potential roles of D-type cyclins in such diverse pulmonary processes as non-small cell lung carcinoma, fibroproliferative repair, diffuse alveolar damage, and asthma (3).
Classic clinical descriptions of asthma have focused on reversible airway narrowing resulting in airflow obstruction and the associated symptoms of cough, wheeze, and dyspnea. Whereas reversibility of airflow obstruction has generally been used to distinguish "asthma" from other conditions traditionally associated more with chronic obstructive pulmonary disease, accumulating evidence indicates that patients with long-standing and severe reversible airway obstruction may progress to exhibit fixed airway narrowing over a period of years (7). Such fixed airway obstruction in long-term asthmatics has been strongly tied to architectural remodeling of the affected airways, with a predominant increase in both the number of airway smooth muscle cells and the thickness of the associated smooth muscle layer. Animal models of airway disease demonstrate marked increases in smooth muscle DNA synthesis after antigenic challenge (8). In addition, patients dying of fatal asthma have been shown to have greater than a threefold increase in both the number of smooth muscle cells and in the airway smooth muscle cross-sectional area compared with patients succumbing to nonasthmatic disorders (9). It has been argued that thickening of the airway smooth muscle layer becomes mainly responsible for airflow obstruction in patients with severe and prolonged airway disease, largely on a geometric basis.
Recent investigations have focused on regulation of airway smooth muscle cell proliferation, in an attempt to better understand airway remodeling that occurs during asthma and other diseases. Mitogenic proliferation of tracheal myocytes has long been known to be regulated by the extracellular signal-related kinase (ERK) and through protein kinase C pathways (10). Additional studies indicate that ERK and the Rho family GTPase protein Rac1 function as upstream activators of the cyclin D1 promoter, and that the intracellular serine/threonine mitogen activated protein kinase (MAPK) family proteins are also active in regulation of DNA synthesis of airway smooth muscle cells (11). More recently, phosphatidylinositol 3-kinase (PI-3K)-related activity has been investigated as a potent second messenger signaling pathway influencing proliferation of smooth muscle cells. It has been demonstrated that PI-3K activity was proportional to the mitogenic proliferative responses of cultured bovine airway smooth muscle cells (12). In addition, wortmannin inhibition of PI-3K activity dramatically decreased DNA synthesis in these cultured myocytes (13). Further studies document that stimulation of cultured smooth muscle cells with platelet-derived growth factor (PDGF) or thrombin leads to a prompt activation of PI-3K (14). It has been suggested that the downstream regulator of PI-3K control over cell-cycle progression may involve p70s6K, a protein activated by PI-3K, which is essential for transition of the cell from G1 into the S phase of the cell cycle (15).
The PI-3K enzyme family is a ubiquitous signaling system implicated in mitogenic cell proliferation and differentiation, activation of leukocytes, cytoskeletal rearrangement, and vesicular traffic and cell survival. The PI-3K enzymes are cytosolic proteins activated through G protein-coupled and tyrosine kinase-linked receptors. Activated PI-3K enzymes act to phosphorylate membrane- associated phosphatidylinositol lipids, with the resulting phosphatidylinositol (3,4,5)triphosphate acting as a second messenger to initiate a number of diverse downstream signaling events. Class IA PI-3Ks are heterodimers composed of a catalytic p110 subunit and a regulatory subunit (either p50, p55, p85, or p101). As mentioned previously, PI-3K modulation of rac and p70s6K activity exerts significant control over cell-cycle progression.
In the current investigation, Page and colleagues have further investigated the role of PI-3K in the regulation of cyclin D1 expression in cultured bovine tracheal myocytes (16). They demonstrate that PI-3K activity of myocytes is activated by PDGF and inhibited by the PI-3K inhibitors wortmannin and LY294002. Inhibitors of PI-3K also decreased cyclin D1 promoter activity, protein abundance, and myocyte DNA replication. Furthermore, Page and coworkers demonstrated that overexpression of the catalytically active subunit of PI-3K (p110PI-3KCAAX) was sufficient to activate the cyclin D1 promoter. In contrast, inhibitors of PI-3K failed to suppress PDGF-induced ERK activation, and overexpression of the active catalytic subunit of this enzyme did not lead to activation of ERK. These studies further revealed that inhibitors of Rac1 signaling suppress cyclin D1 promoter activation through the overexpression of the catalytically active p110PI-3KCAAX subunit. PDGF, PI-3K, and Rac1 each were shown to activate the cyclin D1 promoter at the cAMP response element binding protein (CREB)/activating transcription factor (ATF-2) binding site. These investigators conclude that PI-3K regulates transcription from the cyclin D1 promoter and DNA synthesis in an ERK-independent fashion. The data additionally support that PI-3K and Rac1 regulate airway smooth muscle cell-cycle progression through common cis-regulatory elements in the cyclin D1 promoter.
The current study by Page and coworkers goes a long way toward better defining the mechanisms of PI-3K-related signaling pathways in the control of smooth muscle cell proliferation. The current investigations also strongly support that two independent signaling pathways, namely mediated through ERK and through the PI-3K-related system, are both intimately involved in smooth muscle cell growth regulation. Successful therapeutic manipulation of these systems to alter smooth muscle proliferation and remodeling during advanced airway disease will require additional understanding of all elements of downstream regulation of both cyclin D1 expression, as well as the activation of its Cdk4 partner and other cyclin-dependent kinases mediating regulation of cell-cycle progression in smooth muscle cells.
| |
Footnotes |
|---|
Address correspondence to: Dr. Andrew Limper, 601C Guggenheim Building, Rochester, MN 55905. E-mail: limper.andrew{at}mayo.edu
(Received in original form August 17, 2000).
Abbreviations cdks, cyclic-dependent kinases; ERK, extracellular signal-related kinase; PDGF, platelet-derived growth factor; PI-3K, phosphatidylinositol 3-kinase.
| |
References |
|---|
|
Top
References
|
|---|
1. MacLachlan, T. K., N. Sang, and A. Giordano. 1995. Cyclins, cyclin-dependent kinases and cdk inhibitors: implications in cell cycle control and cancer. Crit. Rev. Eukaryotic Gene Expr. 5: 127-156 [Medline].
2. Lingfei, K., Y. Pingzhang, L. Zhengguo, G. Jianhua, and Z. Yaowu. 1998. A study on p16, pRb, cdk4 and cyclinD1 expression in non-small cell lung cancers. Cancer Lett. 130: 93-101 [Medline].
3.
Caputi, M.,
A. M. Groeger,
V. Esposito,
C. Dean,
A. De Luca,
C. Pacilio,
M. R. Muller,
G. G. Giordano,
F. Baldi,
E. Wolner, and
A. Giordano.
1999.
Prognostic role of cyclin D1 in lung cancer: relationship to proliferating cell nuclear antigen.
Am. J. Respir. Cell Mol. Biol.
20:
746-751
4. Scovassi, A. I., L. A. Stivala, L. Rossi, L. Bianchi, and E. Prosperi. 1997. Nuclear association of cyclin D1 in human fibroblasts: tight binding to nuclear structures and modulation by protein kinase inhibitors. Exp. Cell Res. 237: 127-134 [Medline].
5.
Naureckas, E. T.,
I. M. Ndukwu,
A. J. Halayko,
C. Maxwell,
M. B. Hershenson, and
J. Solway.
1999.
Bronchoalveolar lavage fluid from asthmatic subjects is mitogenic for human airway smooth muscle.
Am. J. Respir. Crit.
Care Med.
160:
2062-2066
6. Adamson, A., S. Perkins, E. Brambilla, S. Tripp, J. Holden, and W. Travis. 1999. Proliferation, C-myc, and cyclin D1 expression in diffuse alveolar damage: potential roles in pathogenesis and implications for prognosis. Hum. Pathol. 30: 1050-1057 [Medline].
7. Burrows, B.. 1991. Epidemiologic evidence for different types of chronic airflow obstruction. Am. Rev. Respir. Dis. 143: 1452-1455 [Medline].
8. Panettieri, R. A., Jr., R. K. Murray, A. J. Eszterhas, G. Bilgen, and J. G. Martin. 1998. Repeated allergen inhalations induce DNA synthesis in airway smooth muscle and epithelial cells in vivo. Am. J. Physiol. 274(3, Pt. 1):L417-L424.
9. Heard, B. E., and S. Hossain. 1973. Hyperplasia of bronchial smooth muscle in asthma. J. Pathol. 110: 319-332 .
10. Karpova, A. Y., M. K. Abe, J. Li, P. T. Liu, J. M. Rhee, W. L. Kuo, and M. B. Hershenson. 1997. MEK1 is required for PDGF-induced ERK activation and DNA synthesis in tracheal myocytes. Am. J. Physiol. 272(3, Pt 1):L558-L565.
11.
Page, K.,
J. Li,
J. A. Hodge,
P. T. Liu,
T. L. Vanden,
Hoek,
L. B. Becker,
R. G. Pestell,
M. R. Rosner, and
M. B. Heshenson.
1999.
Characterization of a
Rac1 signaling pathway to cyclin D(1) expression in airway smooth muscle
cells.
J. Biol. Chem.
274:
22065-22071
12. Scott, P. H., C. M. Belham, J. al-Hafidh, E. R. Chilvers, A. J. Peacock, G. W. Gould, and R. Plevin. 1996. A regulatory role for cAMP in phosphatidylinositol 3-kinase/p70 ribosomal S6 kinase-mediated DNA synthesis in platelet-derived-growth-factor-stimulated bovine airway smooth-muscle. Biochem. J. 318: 965-971 .
13.
Cardenas, M. E.,
M. C. Cruz,
M. Del Poeta,
N. Chung,
J. R. Perfect, and
J. Heitman.
1999.
Antifungal activities of antineoplastic agents: Saccharomyces cerevisiae as a model system to study drug action.
Clin. Microbiol. Rev.
12:
583-611
14.
Walker, T. R.,
S. M. Moore,
M. F. Lawson,
R. A. Panettieri Jr., and
E. R. Chilvers.
1998.
Platelet-derived growth factor-BB and thrombin activate
phosphoinositide 3-kinase and protein kinase B: role in mediating airway
smooth muscle.
Mol. Pharmacol.
54:
1007-1015
15. Krymskaya, V. P., R. B. Penn, M. J. Orsini, P. H. Scott, R. J. Plevin, T. R. Walker, A. J. Esaterhas, Y. Amrani, E. R. Chilvers, and R. A. Panettieri, Jr. 1999. Phosphatidylinositol 3-kinase mediates mitogen-induced human airway smooth muscle cell proliferation. Am. J. Physiol. 277(1, Pt. 1):L65-L78.
16.
Page, K.,
J. Li,
Y. Wang,
S. Kartha,
R. G. Pestell, and
M. B. Hershenson.
2000.
Regulation of cyclin D1 expression and DNA synthesis by phosphatidylinositol 3-kinase in airway smooth muscle cells.
Am. J. Respir. Cell Mol.
Biol.
23:
436-443
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Proc. Am. Thorac. Soc. | Am. J. Respir. Crit. Care Med. |