Publications by authors named "Robert I Seed"

Article Synopsis
  • TGF-β is a crucial protein involved in development and immunity, usually expressed in a latent form associated with its prodomain and presented on immune cells via GARP.
  • Recent findings indicate that TGF-β can signal without needing to fully dissociate from its latent form, challenging existing beliefs.
  • New research using advanced microscopy shows that the binding of integrin αvβ8 can alter the structure of latent TGF-β, allowing it to activate signaling pathways without being released, and this mechanism may apply to other similar receptor/ligand systems.
View Article and Find Full Text PDF

Transforming growth factor beta (TGF-β) is a multi-functional cytokine that plays a significant role in multiple diseases, including fibrosis and tumor progression. Whilst the biologic effects of TGF-β are well characterized, it is unclear how TGF-β signaling is regulated to impart specific responses within certain cell types. One mechanism of regulation may be through TGF-β activation, since TGF-β is always expressed in a latent form (L-TGF-β).

View Article and Find Full Text PDF

Macrophages are paracrine signalers that regulate tissular responses to injury through interactions with parenchymal cells. Connexin hemichannels have recently been shown to mediate efflux of ATP by macrophages, with resulting cytosolic calcium responses in adjacent cells. Here we report that lung macrophages with deletion of connexin 43 (Mac) had decreased ATP efflux into the extracellular space and induced a decreased cytosolic calcium response in co-cultured fibroblasts compared to WT macrophages.

View Article and Find Full Text PDF

Alveolar formation requires coordinated movement and interaction between alveolar epithelial cells, mesenchymal myofibroblasts, and endothelial cells/pericytes to produce secondary septa. These processes rely on the acquisition of distinct cellular properties to enable ligand secretion for cell-cell signaling and initiate morphogenesis through cellular contraction, cell migration, and cell shape change. In this study, we showed that mitochondrial activity and distribution play a key role in bestowing cellular functions on both alveolar epithelial cells and mesenchymal myofibroblasts for generating secondary septa to form alveoli in mice.

View Article and Find Full Text PDF

Antiandrogen therapy is a primary treatment for patients with metastasized prostate cancer. Whilst the biologic mechanisms of antiandrogens have been extensively studied, the operating protocols used for the characterization of these drugs were not identical, limiting their comparison. Here, the antiandrogens Bicalutamide, Enzalutamide, Apalutamide, and Darolutamide were systematically compared using identical experimental setups.

View Article and Find Full Text PDF

Regulatory T cells (T) that promote tumor immune evasion are enriched in certain tumors and correlate with poor prognosis. However, mechanisms for T enrichment remain incompletely understood. We described a mechanism for T enrichment in mouse and human tumors mediated by the αvβ8 integrin.

View Article and Find Full Text PDF

Integrin αvβ8 binds with exquisite specificity to latent transforming growth factor-β (L-TGF-β). This binding is essential for activating L-TGF-β presented by a variety of cell types. Inhibiting αvβ8-mediated TGF-β activation blocks immunosuppressive regulatory T cell differentiation, which is a potential therapeutic strategy in cancer.

View Article and Find Full Text PDF

Urothelial cancer (UC) is one of the most common cancers in Europe and is also one of the costliest to treat. When first line therapies show initial success, around 50% of cancers relapse and proceed to metastasis. In this study we assessed the Protein inhibitor of activated signal transducers and activators of transcription (PIAS)1 as a potential therapeutic target in urothelial cancer.

View Article and Find Full Text PDF

Loss of latexin (LXN) expression negatively correlates with the prognosis of several human cancers. Despite association with numerous processes including haematopoietic stem cell (HSC) fate, inflammation and tumour suppression, a clearly defined biological role for LXN is still lacking. Therefore, we sought to understand LXN expression and function in the normal and malignant prostate to assess its potential as a therapeutic target.

View Article and Find Full Text PDF

TGF-β is a promising immunotherapeutic target. It is expressed ubiquitously in a latent form that must be activated to function. Determination of where and how latent TGF-β (L-TGF-β) is activated in the tumor microenvironment could facilitate cell- and mechanism-specific approaches to immunotherapeutically target TGF-β.

View Article and Find Full Text PDF

Prostate cancer research is hampered by the lack of in vivo preclinical models that accurately reflect patient tumour biology and the clinical heterogeneity of human prostate cancer. To overcome these limitations we propagated and characterised a new collection of patient-derived prostate cancer xenografts. Tumour fragments from 147 unsupervised, surgical prostate samples were implanted subcutaneously into immunodeficient Rag2-/-γC-/- mice within 24 hours of surgery.

View Article and Find Full Text PDF

The PTTG1-binding factor (PBF) is a transforming gene capable of eliciting tumor formation in xenograft models. However, the precise role of PBF in tumorigenesis and its prognostic value as a cancer biomarker remain largely uncharacterised, particularly in malignancies outside the thyroid. Here, we provide the first evidence that PBF represents a promising prognostic marker in colorectal cancer.

View Article and Find Full Text PDF

Airway remodeling, caused by inflammation and fibrosis, is a major component of chronic obstructive pulmonary disease (COPD) and currently has no effective treatment. Transforming growth factor-β (TGF-β) has been widely implicated in the pathogenesis of airway remodeling in COPD. TGF-β is expressed in a latent form that requires activation.

View Article and Find Full Text PDF

The PTTG1-binding factor (PBF/PTTG1IP) has an emerging repertoire of roles, especially in thyroid biology, and functions as a protooncogene. High PBF expression is independently associated with poor prognosis and lower disease-specific survival in human thyroid cancer. However, the precise role of PBF in thyroid tumorigenesis is unclear.

View Article and Find Full Text PDF
Article Synopsis
  • The human pituitary tumor transforming gene (hPTTG) is a proto-oncogene linked to tumor growth, regulated by cyclin-dependent kinase 2 (CDC2) and specificity protein 1 (SP1).
  • *In thyroid cells, growth factors like EGF, TGFα, and IGF-1 boost hPTTG expression and phosphorylation, activating key signaling pathways independently of CDC2 and SP1.
  • *Transgenic and knockout mouse models showed that hPTTG influences thyroid cell growth and signaling, suggesting its significant role in promoting cell transformation and growth through autocrine mechanisms.
View Article and Find Full Text PDF

The ability of adenovirus early region proteins, E1B-55K and E4orf6, to usurp control of cellular ubiquitin ligases and target proteins for proteasome-dependent degradation during infection is well established. Here we show that the E4 gene product, E4orf3 can, independently of E1B-55K and E4orf6, target the transcriptional corepressor transcriptional intermediary factor 1γ (TIF1γ) for proteasome-mediated degradation during infection. Initial mass spectrometric studies identified TIF1 family members-TIF1α, TIF1β, and TIF1γ-as E1B-55K-binding proteins in both transformed and infected cells, but analyses revealed that, akin to TIF1α, TIF1γ is reorganized in an E4orf3-dependent manner to promyelocytic leukemia protein-containing nuclear tracks during infection.

View Article and Find Full Text PDF
Article Synopsis
  • PBF (PTTG-binding factor) is a proto-oncogene linked to breast and thyroid tumors, and researchers created a mouse model to study its effects specifically in the thyroid gland.
  • In PBF-Tg mice, the thyroid gland enlarged significantly with hyperplastic and macrofollicular lesions, while crucial genes for radioiodine therapy showed reduced expression.
  • The study also found that increasing PBF levels corresponded with cell proliferation in both mice and human thyroid tissue, highlighting PBF’s role in thyroid disorders and its potential impact on treatment effectiveness.
View Article and Find Full Text PDF