Deregulation of Negative Controls on TGF-β1 Signaling in Tumor Progression

Abstract

The multi-functional cytokine transforming growth factor-β1 (TGF-β1) has growth inhibitory and anti-inflammatory roles during homeostasis and the early stages of cancer. Aberrant TGF-β activation in the late-stages of tumorigenesis, however, promotes development of aggressive growth characteristics and metastatic spread. Given the critical importance of this growth factor in fibrotic and neoplastic disorders, the TGF-β1 network is subject to extensive, multi-level negative controls that impact receptor function, mothers against decapentaplegic homolog 2/3 (SMAD2/3) activation, intracellular signal bifurcation into canonical and non-canonical pathways and target gene promotor engagement. Such negative regulators include phosphatase and tensin homologue (PTEN), protein phosphatase magnesium 1A (PPM1A), Klotho, bone morphogenic protein 7 (BMP7), SMAD7, Sloan-Kettering Institute proto-oncogene/ Ski related novel gene (Ski/SnoN), and bone morphogenetic protein and activin membrane-bound Inhibitor (BAMBI). The progression of certain cancers is accompanied by loss of expression, overexpression, mislocalization, mutation or deletion of several endogenous repressors of the TGF-β1 cascade, further modulating signal duration/intensity and phenotypic reprogramming. This review addresses how their aberrant regulation contributes to cellular plasticity, tumor progression/metastasis and reversal of cell cycle arrest and discusses the unexplored therapeutic value of restoring the expression and/or function of these factors as a novel approach to cancer treatment.

Protein phosphatase Mg 2+ /Mn 2+ dependent‐1A and PTEN deregulation in renal fibrosis: Novel mechanisms and co‐dependency of expression

“…[36][37][38] Thus, this paper and the findings from other groups contribute to the emerging recognition that both miRNAdependent (eg, miR-21) and independent (eg, ubiquitindriven protein degradation) regulatory networks contribute to the pathological PTEN loss evident in various forms of kidney disease. 26,39,40 Interestingly, idiopathic PTEN and PPM1A loss also occurs in various cancers, 25 which warrants assessments as to whether PPM1A and PTEN cooperation is exclusive to renal fibrogenesis.…”

“…Although the TGF‐β1 network is subject to extensive negative control, the expression of several repressors of the TGF‐β1 signaling pathway (eg, SMAD7, Ski, SnoN) is attenuated following renal injury, exacerbating disease progression . Recent findings identified phosphatase and tensin homolog (PTEN), an established tumor suppressor and an inhibitor of the PI3K/Akt signaling pathway, has recently emerged as a novel regulator of the TGF‐β1/ SMAD2/3 pathway during cancer progression and tissue fibrogenesis . PTEN is downregulated during renal injury and attenuation of PTEN levels in the glomeruli of the diabetic kidney promotes Akt‐dependent glomerular hypertrophy .…”

“…[21][22][23] Recent findings identified phosphatase and tensin homolog (PTEN), an established tumor suppressor and an inhibitor of the PI3K/Akt signaling pathway, has recently emerged as a novel regulator of the TGF-β1/ SMAD2/3 pathway during cancer progression and tissue fibrogenesis. 24,25 PTEN is downregulated during renal injury and attenuation of PTEN levels in the glomeruli of the diabetic kidney promotes Akt-dependent glomerular hypertrophy. 26 Proximal tubule-specific PTEN ablation leads to renal hypertrophy through PI3K/mTORC2/EGFR/Akt signaling.…”

TGF‐β1–p53 cooperativity regulates a profibrotic genomic program in the kidney: molecular mechanisms and clinical implications

“…One model proposes that Numb dissociates MDM2-p53 complexes or inhibits complex formation (89), effectively maintaining p53 engagement of target genes. Numb also promotes ubiquitination of phosphatase and tensin homolog, a regulator of the C-terminal SMAD phosphatase protein phosphatase, Mg2 + /Mn2 + dependent 1A (92)(93)(94)(95). Collectively, these findings suggest that Numb-mediated attenuation of MDM2-dependent p53 degradation coupled with phosphatase and tensin homolog loss and the resulting maintenance of p-SMAD2 and 3 signaling may predispose the kidney to development of tubulointerstitial fibrosis (94,95).…”

Prognostic Values of Transforming Growth Factor-Beta Subtypes in Ovarian Cancer

“…In addition, immunohistochemistry results confirmed a significantly higher expression of TGF-β2 in ovarian carcinoma samples than in normal ovarian samples. TGF-β1 is a powerful immunosuppressant in humans that inhibits cell growth and is an anti-inflammatory during the early stages of carcinomas [15]. Abnormal activation of TGF-β1 in the late stages of gastric cancer has been revealed to promote the development of aggressive growth and metastases of primary gastric carcinomas by regulating paracrine effects on mesenchymal cells, vascular endothelial cells, and lymphocytes [16].…”