Changes In TGF-beta Expression Research Articles

The cyclin kinase inhibitor p57kip2 regulates TGF- -induced compensatory tubular hypertrophy: effect of the immunomodulator AS101

Compensatory tubular cell hypertrophy following unilateral nephrectomy is a cell cycle-dependent process. Our previous study showed that treatment of unilaterally nephrectomized rats with the immunomodulator AS101 partially inhibits compensatory hypertrophy of the remaining kidneys through the inhibition of IL-10-induced TGF-beta secretion by mesangial cells. The present study is focused on understanding the intracellular mechanism(s) of this phenomenon. A total of 120 male Sprague-Dawley rats were unilaterally nephrectomized or sham-operated and treated with AS101 or PBS. Kidney weight and protein/DNA ratio were assessed for each experimental animal. The expression of TGF-beta, PCNA, CDK 2, pRb, ppRb, p21(Waf1), p27(kip1) and p57(kip2) proteins in renal tissues was determined by western blot analysis and immunohistochemistry, and the immunoprecipitation of cyclin E complexes was performed. Compensatory renal growth is initiated by proliferation of resident renal cells that precedes hypertrophy. Changes in TGF-beta expression were positively correlated with the amounts of p57(kip2), but not with p21(Waf1) and p27(kip1) expression in the remaining kidneys. Moreover, there was a marked abundance of p57(kip2) but not p21(Waf1) and p27(kip1) binding to the cyclin E complex in PBS-treated unilaterally nephrectomized rats compared to sham-operated animals. Treatment of uninephrectomized rats with AS101 reduced kidney weight and protein/DNA ratio, inhibited TGF-beta and p57(kip2) expression in the remaining kidneys, and decreased the level of p57(kip2) binding to cyclin E complexes. These results demonstrate that TGF-beta-induced compensatory tubular cell hypertrophy is regulated in vivo by p57(kip2) but not by the p21(Waf1) and p27(kip1) cyclin kinase inhibitor proteins.

Temporal changes in expression of TGF-beta isoforms in mouse lung exposed to oxygen.

Oxygen-induced pulmonary injury is associated with cell death and a significant inflammatory response. Because transforming growth factor (TGF)-beta is a potent modulator of the immune response, changes in expression of the three TGF-beta (beta 1, beta 2, beta 3) isoforms was determined in lungs of adult mice exposed to > 95% oxygen. TGF-beta 1 immunostaining within cuboidal nonciliated bronchiolar epithelial cells was increased within 3 h of oxygen exposure and continued to increase for 48 h before decreasing to control levels by 72 h. A similar but less marked change that was morphologically consistent with alveolar type II cells was observed in granulated cells. Immunostaining for TGF-beta 2 and TGF-beta 3 revealed a similar change in bronchiolar epithelium with little change observed in the alveolar epithelium. Immunohistochemical changes in TGF-beta expression were not observed in any other pulmonary cells. Northern blot analysis of total lung RNA revealed that expression of the TGF-beta mRNA was not markedly altered over the 72-h exposure period. Exposure to > 95% oxygen resulted in cell type-specific posttranscriptional changes in TGF-beta isoforms in the lung.

Changes in expression of transforming growth factor beta mRNA isoforms in patients undergoing tamoxifen therapy

Tumour was obtained from 37 patients with oestrogen receptor-positive breast cancer, before and during treatment with tamoxifen, and examined qualitatively and semi-qualitatively for mRNA of the three mammalian TGF-beta isoforms. Levels of TGF-beta isoforms were then correlated with tumour response to tamoxifen, as assessed by monthly ultrasound. A high incidence of expression by each isoform was found in tumour material taken both before and during treatment. Semiquantitative assessment of mRNA showed that in the majority of tumours, expression of TGF-beta s did not change markedly with treatment, i.e. beyond that which might have been caused by method reproducibility and tumour heterogeneity (variations of < 100% between pre- and post-treatment samples). In those displaying significant variation with treatment, expression of TGF-beta 1 and -beta 3 increased or decreased in equal numbers, whereas TGF-beta 2 expression tended to increase with treatment. Subdividing tumours by clinical response revealed no significant association between changes in expression of TGF-beta 1 and TGF-beta 3. There was, however, a significant correlation between changes in expression of TGF-beta 2 and response (P = 0.018). Thus, of 15 responding tumours displaying substantial changes, 11 showed an increase in TGF-beta 2 expression with treatment, whereas none of the non-responding tumours were associated with increased expression. While not providing evidence for a generalised increase in TGF-beta expression with tamoxifen treatment, the present study suggests that response to tamoxifen therapy may be associated with an increase in expression of specific TGF-beta isoforms in some, but not all, tumours.

Immunocytochemically Detectable TGF-β Associated with Malignancy in Thyroid Epithelial Neoplasia

The possible role of changes in TGF-beta expression in the multistage development of thyroid cancer was assessed. The presence of TGF-beta 1 in thyroid epithelial cells was analyzed in sections of normal and tumor tissue using an immunoperoxidase technique employing an antibody directed against the amino-terminal 30 amino acids of mature TGF-beta 1. Specific immunostaining was clearly detected in epithelial cells in 58% of malignant thyroid tumours (including follicular, papillary, and anaplastic variants). However, no positive cells were seen in any of 7 benign tumors nor in any normal thyroid epithelium. Within the cancer group as a whole, there was no significant correlation with pathological grade or clinical stage of tumor but in one subgroup--follicular carcinomas--a significant association was noted between TGF-beta immunostaining and the presence of a specific mutation of the H-ras oncogene (codon 61, gln----arg). We conclude that a major alteration in expression of TGF-beta occurs specifically in the malignant stage of tumor development in thyroid follicular epithelium and speculate on its possible role in this process.