Nancy J. Sipes

Selective inhibition of growth-related gene expression in murine keratinocytes by transforming growth factor beta.

Transforming growth factor beta (TGF beta) is a potent inhibitor of epithelial cell proliferation. A nontumorigenic epidermal growth factor (EGF)-dependent epithelial cell line, BALB/MK, is reversibly growth arrested by TGF beta. TGF beta will also abrogate EGF-stimulated mitogenesis of quiescent BALB/MK cells. Increased levels of calcium (greater than 1.0 mM) will induce differentiation in BALB/MK cells; in contrast, TGF beta-mediated growth inhibition does not result in induction of terminal differentiation. In the present study, the effects of TGF beta and calcium on growth factor-inducible gene expression were examined. TGF beta markedly decreased c-myc and KC gene expression in rapidly growing BALB/MK cells and reduced the EGF induction of c-myc and KC in a quiescent population of cells. TGF beta exerted its control over c-myc expression at a posttranscriptional level, and this inhibitory effect was dependent on protein synthesis. TGF beta had no effect on c-fos gene expression, whereas 1.5 mM calcium attenuated EGF-induced c-fos expression in quiescent cells. Expression of beta-actin, however, was slightly increased in both rapidly growing and EGF-restimulated quiescent BALB/MK cells treated with TGF beta. Thus, in this system, TGF beta selectively reduced expression of certain genes associated with cell proliferation (c-myc and KC), and at least part of the TGF beta effect was at a posttranscriptional level.

Transforming Growth Factor β in the Control of Epidermal Proliferation

Transforming growth factor beta is a polypeptide growth factor with a multiplicity of diverse biologic effects. Increasingly, data support a role for TGF beta in the autocrine regulation of normal epithelial cell growth (Figure 1). Definition of the normal pathways for growth stimulation and inhibition of epithelial cell growth by autocrine peptides like TGF beta and TGF alpha undoubtedly will increase understanding of normal growth and development, embryogenesis, wound repair, and tumorigenesis.

Biological effects of transforming growth factors

Transforming growth factors (TGFs) were originally defined by their biological effects on fibroblastic cells (for review see Goustin et al. 1986). These effects included induction of morphological transformation in monolayer culture and Stimulation of colony formation in soft agar. While the early studies with TGFα were somewhat misleading with respect to the function of these factors, they did lead to the purification and cloning of two important growth-regulatory molecules, TGFα and TGFβ. Interestingly, one of these factors (TGFα) is a potent mitogen for a wide variety of cell types, while the other (TGFβ) is the most potent growth-inhibitory Polypeptide known for most cell types (Goustin et al. 1986).

Biological characterization of an acid-sensitive growth factor from human platelets: role in the proliferation of human melanoma and bovine endothelial cells.

An acid-sensitive growth factor for human melanoma has been partially purified from human platelets. TSK gel filtration HPLC provides a molecular weight estimation of 60,000 daltons. This factor is not only mitogenic for human melanoma, but also stimulates 3H-thymidine uptake and increases the number of bovine aortic endothelial cells, while fibroblasts are nonresponsive. Radioiodination of active HPLC fraction has been accomplished. The human melanoma cell line, M1RW5 demonstrates specific, time-dependent binding of the labeled protein. These studies suggest that the growth of human melanoma may in part be regulated by a newly described growth factor present in human platelets.

E64d treatment improves outcomes in animal models of traumatic brain injury, ischemia and Alzheimer's disease through inhibiting cathepsin B

physiological and pathological settings in response to vaccination. However, the actual role of Tregs in the pathophysiology of AD remains unknown. We analyzed the impact of Tregs on disease progression in a murine model of AD. Methods: APPPS1 mice were depleted of Treg cells by injecting antiCD25 antibodies, and the impact of Treg depletion on the neuropathology and cognitive deficits was evaluated. Results: Depletion of Treg cells accelerated the onset of cognitive deficits in APPPS1 mice. Alteration in spatial memory was detected starting from 7months in Treg-depleted animals, while PBS-treated APPPS1 mice were not yet cognitively impaired as compared to wild-type animals. Early cognitive impairment in Treg-depleted mice was correlated with alterations in the neuroinflammatory response that is associated with disease progression. Conclusions: Treg cells play a beneficial role in the pathophysiology of AD and delay disease progression in a murine model of the disease. These data open new perspectives in the development of Treg-based innovative immunotherapy approaches for the treatment of AD.