The cyclin-dependent kinase inhibitor, p21 WAF1 , promotes angiogenesis by repressing gene transcription of thioredoxin-binding protein 2 in cancer cells

Kuljaca, Selena; Liu, Tao; Dwarte, Tanya; Kavallaris, Maria; Haber, Michelle; Norris, Murray D.; Juan, Manel; Marshall, Glenn M.

doi:10.1093/carcin/bgp225

Cited by 26 publications

(17 citation statements)

References 24 publications

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“…88 The cell cycle inhibitor and tumor suppressor p21(WAF1) also suppresses TXNIP gene transcription leading to increases in TRX activity, EC migration, vascular network formation and invasion. 89 …”

Section: The Thioredoxin Systemmentioning

confidence: 99%

The Emerging Role of the Thioredoxin System in Angiogenesis

Dunn

Buckle

Cooke

et al. 2010

ATVB

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Notwithstanding a multitude of studies, the mechanisms of angiogenesis remain incompletely understood. Increasing evidence suggests that cellular redox homeostasis is an important regulator of angiogenesis. The thioredoxin (TRX) system functions as an endogenous antioxidant that can exert influence over endothelial cell (EC) function via modulation of cellular redox status. It has become apparent that the cytosolic thioredoxin-1 (TRX1) isoform participates in both canonical and novel angiogenic signaling pathways, and may represent an avenue for therapeutic exploitation. Recent studies have further identified a role for the mitochondrial isoform thioredoxin-2 (TRX2) in ischemia-induced angiogenesis. Thioredoxin interacting protein (TXNIP) is the endogenous inhibitor of TRX redox activity that has been implicated in growth factor-mediated angiogenesis. As TXNIP is strongly induced by glucose, this molecule could be of consequence to disordered angiogenesis manifest in diabetes mellitus. This review will focus on data implicating the TRX system in EC homeostasis and angiogenesis.

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Section: The Thioredoxin Systemmentioning

confidence: 99%

The Emerging Role of the Thioredoxin System in Angiogenesis

Dunn

Buckle

Cooke

et al. 2010

ATVB

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“…Upregulation of the proangiogenic insulin-like growth factor-1 (IGF-1) in the lungs of infants with fatal BPD through histone modification after postnatal mechanical ventilation may reflect a response to injury in the pulmonary vasculature [70-72]. Pulmonary histone deacetylase activity is decreased in experimental BPD with resultant upregulation of p21, a cyclin-dependent kinase that may be proangiogenic [73, 74]. In both mice and human lung tissues, DNA methylation, another form of epigenetic regulation, has been shown to alter expression of genes associated with lung development and alveolar septation including a number of genes in angiogenic pathways [75].…”

Section: Introductionmentioning

confidence: 99%

Impaired Pulmonary Vascular Development in Bronchopulmonary Dysplasia

Baker

Abman²

2015

Neonatology

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Bronchopulmonary dysplasia (BPD), the chronic lung disease associated with preterm birth, results from the disruption of normal pulmonary vascular and alveolar growth. Though BPD was once described as primarily due to postnatal injury from mechanical ventilation and oxygen therapy after preterm birth, it is increasingly appreciated that BPD results from antenatal and perinatal factors that interrupt lung development in infants born at the extremes of prematurity. The lung in BPD consists of a simplified parenchymal architecture that limits gas exchange and leads to increased cardiopulmonary morbidity and mortality. This review outlines recent advances in the understanding of pulmonary vascular development and describes how the disruption of these mechanisms results in BPD. We point to future therapies that may augment postnatal vascular growth to prevent and treat this severe chronic lung disease.

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“…However the differences between in vivo radiosensitivity and p21 expression can be studied using the model systems we have developed. Interestingly, Kuljaca et al [30] have shown that p21 promotes angiogenesis so the interaction of p21 with angiogenesis at higher doses needs further study. Importantly, the creation of an appropriate tumor microenvironment that would enhance tumor response may be achievable using chemical or biological agents.…”

Section: Discussionmentioning

confidence: 99%

Tumor response to radiotherapy is dependent on genotype-associated mechanisms in vitro and in vivo

et al. 2010

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BackgroundWe have previously shown that in vitro radiosensitivity of human tumor cells segregate non-randomly into a limited number of groups. Each group associates with a specific genotype. However we have also shown that abrogation of a single gene (p21) in a human tumor cell unexpectedly sensitized xenograft tumors comprised of these cells to radiotherapy while not affecting in vitro cellular radiosensitivity. Therefore in vitro assays alone cannot predict tumor response to radiotherapy.In the current work, we measure in vitro radiosensitivity and in vivo response of their xenograft tumors in a series of human tumor lines that represent the range of radiosensitivity observed in human tumor cells. We also measure response of their xenograft tumors to different radiotherapy protocols. We reduce these data into a simple analytical structure that defines the relationship between tumor response and total dose based on two coefficients that are specific to tumor cell genotype, fraction size and total dose.MethodsWe assayed in vitro survival patterns in eight tumor cell lines that vary in cellular radiosensitivity and genotype. We also measured response of their xenograft tumors to four radiotherapy protocols: 8 × 2 Gy; 2 × 5Gy, 1 × 7.5 Gy and 1 × 15 Gy. We analyze these data to derive coefficients that describe both in vitro and in vivo responses.ResultsResponse of xenografts comprised of human tumor cells to different radiotherapy protocols can be reduced to only two coefficients that represent 1) total cells killed as measured in vitro 2) additional response in vivo not predicted by cell killing. These coefficients segregate with specific genotypes including those most frequently observed in human tumors in the clinic. Coefficients that describe in vitro and in vivo mechanisms can predict tumor response to any radiation protocol based on tumor cell genotype, fraction-size and total dose.ConclusionsWe establish an analytical structure that predicts tumor response to radiotherapy based on coefficients that represent in vitro and in vivo responses. Both coefficients are dependent on tumor cell genotype and fraction-size. We identify a novel previously unreported mechanism that sensitizes tumors in vivo; this sensitization varies with tumor cell genotype and fraction size.

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The cyclin-dependent kinase inhibitor, p21 WAF1 , promotes angiogenesis by repressing gene transcription of thioredoxin-binding protein 2 in cancer cells

Cited by 26 publications

References 24 publications

The Emerging Role of the Thioredoxin System in Angiogenesis

The Emerging Role of the Thioredoxin System in Angiogenesis

Impaired Pulmonary Vascular Development in Bronchopulmonary Dysplasia

Tumor response to radiotherapy is dependent on genotype-associated mechanisms in vitro and in vivo

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