Elastin is crucial to pulmonary function, yet it appears in the pulmonary vasculature and interstitium late in gestation in large mammals and postnatally in rodents (1). Deletion of the ELN gene in mice produces obstructive arterial disease (2, 3) and disrupts terminal airway branching as well as alveogenesis (4); moreover, several forms of elastic tissue disease collectively known as cutis laxa have mild to fatal pulmonary complications (5). Once elastin has been deposited together with other elements of the elastic fiber, elastin synthesis ceases and turnover is close to nil. However, a program of neosynthesis of elastin can be rapidly activated by pulmonary hypertension and lung injuries leading to fibrosis (6, 7). Among the most potent modulators of elastin production is the pleiotropic growth factor, transforming growth factor (TGF). In this issue, Kucich and coworkers report several novel observations that broaden yet complicate the signal mechanisms by which TGFexerts its effects on elastin mRNA stability (8). Signaling from the heteromeric, serine-threonine kinase TGFreceptors (TGFRs) at the cell surface causes inhibition of epithelial proliferation, epithelial-mesenchymal transformation, chemoattraction of inflammatory cells, immunosuppressive effects, and a particular group of responses that affect extracellular matrix metabolism and recognition. Much interest and excitement has been created by the identification of the Smad group of transducing factors (a condensation of the terms for two gene families involved in TGFsuperfamily signaling: Sma from Caenorhabditis elegans and mothers against decapentaplegic in Drosophila ). The Smad group of transducers, cotransducers, and counter-transducers can transmit signals from the TGFRs directly to nuclear transcription targets. The direct action of these factors on transcriptional machinery has offered relief from the complex networks involved in signaling from tyrosine kinase growth factor receptors such as those recognizing epidermal growth factor, platelet-derived growth factor, and fibroblast growth factor. It’s not that simple. Kucich and colleagues, in a series of papers, have presented persuasive data showing that the ultimate effects of TGFon elastin, fibronectin, and CTGF expression require other downstream signaling pathways (8–13). These data address the concept of TGFsignaling that are not intrinsic to the Smad pathway. The end points in the current paper by Kucich and coworkers are the accumulation of elastin mRNA and secretion of tropoelastin by lung fibroblasts after TGFtreatment. Elastin transcription may be modestly affected by TGFtreatment in some cells, but a series of studies over the past 10 years have implicated mRNA stability as the primary mechanism that regulates elastin mRNA levels and elastin synthesis in connective tissue cells (14–17). TGFcan affect the mRNA stability in a number of other connective tissue genes, including COL1 (18), fibronectin (19), and RHAMM (20). Furthermore, the stability of nonmatrix transcripts such as ribonucleotide reductase R2 appears to be regulated by TGF(21, 22). At least some of the effects of TGFon matrix accumulation are not due to direct action of Smads on matrix genes. This point is amplified and clarified by the present study. Elastin is one of a few proteins whose expression is extensively controlled at a post-transcriptional level (1). Parks and colleagues performed a number of studies on elastin regulation that emphasized the impact of mRNA degradation on regulation of elastin mRNA by vitamin D, steroids, and phorbol ester (24–26). Following on the observation that TGF1 was a strong stimulus for elastin expression (23), Kahari and coworkers showed that this effect was largely due to changes in mRNA stability (15). In contrast, studies of transcriptional regulation of elastin synthesis have identified only a limited number of regulatory factors, some of them negative, and most having a narrow dynamic range (27). The elastin promoter does show modulation by IGF-1 (28–30), and a transgenic mouse strain using a 6-kB human elastin promoter shows reasonably tight temporal and tissue-specific regulation (31). In the developing lung, elastin accumulation sharply rises during the phase of alveolarization, and accumulation is reflected in large increases in elastin mRNA abundance. Studies by Swee and coworkers suggest that elastin transcription is activated during this stage of differentiation, and elastin mRNA stability is high (32). At the cessation of lung development, elastin synthesis and elastin mRNA levels fall to nearly undetectable levels, consistent with the very low turnover rates of elastin during adult life. However, estimates of elastin transcription based on nuclear pre-mRNA suggest that transcription levels—at least in rat lung fibroblasts—remain high throughout adult life, implying that mRNA decay is the predominant regulatory mechanism in the rat lung fibroblast. Thus, the role of TGFand other modulators of RNA stability becomes an important aspect of pulmonary physiology. ( Received in original form December 26, 2001 )