MOLECULAR MECHANISMS UNDERLYING TRANSFORMING GROWTH FACTOR-BETA-INDUCED EXPRESSION OF THE APOLIPOPROTEIN E GENE

Background: Glioblastoma is the most common primary malignant brain tumor. Primary Glioblastoma (PriGO) cells are key drivers of glioblastoma. Senescence is the irreversible growth arrest of cells with continued metabolic activity. Recently, I discovered PriGO cells undergo premature senescence in response to Fetal Bovine Serum (FBS). Determining the underlying molecular mechanisms may allow development of novel therapeutic strategies to decrease the malignant potential of glioblastoma. Methods: Global gene expression changes in PriGO cells treated with serum were analyzed and compared to untreated cells. Senescence was determined by the Senescence-Associated-Beta-Galactosidase (SA-B-Gal) assay. Results: PriGO cells treated with serum demonstrated increased expression of genes in the Transforming Growth Factor Beta (TGF-B) pathway, such as Thrombospondin 1 (TSP1), compared to untreated cells. TGF-B treatment of PriGO cells significantly increased senescence compared to untreated cells. Treatment of PriGO cells with serum and the TGF-B inhibitor SB431542 led to a decrease in senescence compared to serum only treated cells. Treatment of PriGO cells with serum and the TSP1 inhibitor LSKL led to a reduction in senescence compared to serum only treated cells. Conclusions: Our data identifies TGF-B as an important component of serum responsible for inducing senescence in PriGO cells. Furthermore, TGF-B induced senescence in PriGO cells is in part mediated by TSP1.

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Transforming growth factor-beta and malignant melanoma: molecular mechanisms

Journal of Cutaneous Pathology ◽

10.1111/j.0303-6987.2005.00356.x ◽

2005 ◽

Vol 32 (6) ◽

pp. 389-395 ◽

Cited By ~ 26

Author(s):

Mahmoud R. Hussein

Keyword(s):

Growth Factor ◽

Malignant Melanoma ◽

Transforming Growth Factor Beta ◽

Molecular Mechanisms ◽

Transforming Growth Factor ◽

Growth Factor Beta

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Role of PDGF-A expression in the control of vascular smooth muscle cell growth by transforming growth factor-beta.

The Journal of Cell Biology ◽

10.1083/jcb.111.1.239 ◽

1990 ◽

Vol 111 (1) ◽

pp. 239-247 ◽

Cited By ~ 163

Author(s):

R A Majack ◽

M W Majesky ◽

L V Goodman

Keyword(s):

Smooth Muscle ◽

Growth Factor ◽

Vascular Smooth Muscle ◽

Transforming Growth Factor Beta ◽

Molecular Mechanisms ◽

Transforming Growth Factor ◽

De Novo ◽

Tgf Beta ◽

Gene And Protein Expression ◽

Growth Factor Beta

Transforming growth factor-beta (TGF-beta) is a multifunctional regulatory peptide that can inhibit or promote the proliferation of cultured vascular smooth muscle cells (SMCs), depending on cell density (Majack, R. A. 1987. J. Cell Biol. 105:465-471). In this study, we have examined the mechanisms underlying the growth-promoting effects of TGF-beta in confluent SMC cultures. In mitogenesis assays using confluent cells, TGF-beta was found to potentiate the stimulatory effects of serum, PDGF, and basic fibroblast growth factor (bFGF), and was shown to act individually as a mitogen for SMC. In gene and protein expression experiments, TGF-beta was found to regulate the expression of PDGF-A and thrombospondin, two potential mediators of SMC proliferative events. The induction of thrombospondin protein and mRNA was density-dependent, delayed relative to its induction by PDGF and, based on cycloheximide experiments, appeared to depend on the de novo synthesis of an intermediary protein (probably PDGF-A). The relationship between PDGF-A expression and TGF-beta-mediated mitogenesis was investigated, and it was determined that a PDGF-like activity (probably PDGF-A) was the biological mediator of the growth-stimulatory effects of TGF-beta on confluent SMC. The effects of purified homodimers of PDGF-A on SMC replication were investigated, and it was determined that PDGF-AA was mitogenic for cultured SMC, particularly when used in combination with other growth factors such as bFGF and PDGF-BB. The data suggest several molecular mechanisms that may account for the ability of TGF-beta to promote the growth of confluent SMC in culture.

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Structural biology of the TGFβ family

Experimental Biology and Medicine ◽

10.1177/1535370219880894 ◽

2019 ◽

Vol 244 (17) ◽

pp. 1530-1546 ◽

Cited By ~ 3

Author(s):

Erich J Goebel ◽

Kaitlin N Hart ◽

Jason C McCoy ◽

Thomas B Thompson

Keyword(s):

Growth Factor ◽

Signaling Pathway ◽

Structural Biology ◽

Transforming Growth Factor Beta ◽

Molecular Mechanisms ◽

Transforming Growth Factor ◽

Biological Processes ◽

Tgfβ Signaling ◽

Growth Factor Beta ◽

Tgfβ Signaling Pathway

The transforming growth factor beta (TGFβ) signaling pathway orchestrates a wide breadth of biological processes, ranging from bone development to reproduction. Given this, there has been a surge of interest from the drug development industry to modulate the pathway – at several points. This review discusses and provides additional context for several layers of the TGFβ signaling pathway from a structural biology viewpoint. The combination of structural techniques coupled with biophysical studies has provided a foundational knowledge of the molecular mechanisms governing this high impact, ubiquitous pathway, underlying many of the current therapeutic pursuits. This work seeks to consolidate TGFβ-related structural knowledge and educate other researchers of the apparent gaps that still prove elusive. We aim to highlight the importance of these structures and provide the contextual information to understand the contribution to the field, with the hope of advancing the discussion and exploration of the TGFβ signaling pathway. Impact statement The transforming growth factor beta (TGFβ) signaling pathway is a multifacetted and highly regulated pathway, forming the underpinnings of a large range of biological processes. Here, we review and consolidate the key steps in TGFβ signaling using literature rooted in structural and biophysical techniques, with a focus on molecular mechanisms and gaps in knowledge. From extracellular regulation to ligand–receptor interactions and intracellular activation cascades, we hope to provide an introductory base for understanding the TGFβ pathway as a whole.

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