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 D 1 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 (3–6). 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 D 1 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 p70 s6K , 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 membraneassociated 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 com( Received in original form August 17, 2000 )
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Mar 12, 2001
Richard E Tracy 
Open Access