A Small-Molecule E2F Inhibitor Blocks Growth in a Melanoma Culture Model

Ma, Yihong; Kurtyka, Courtney A.; Boyapalle, Sandhya; Sung, Shen Shu; Lawrence, Harshani R.; Guida, Wayne C.; Cress, W. Douglas

doi:10.1158/0008-5472.can-08-0121

Cited by 92 publications

(79 citation statements)

References 28 publications

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“…Treatment of hESCs with the E2F inhibitor HLM006474 (ref. 28) significantly decreased hESC proliferation (Fig. 2d) and led to an increase in cell death (Fig.…”

Section: Rb Activation In Hescs Induces Cell Cycle Arrest and Deathmentioning

confidence: 87%

The RB family is required for the self-renewal and survival of human embryonic stem cells

2012

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The mechanisms ensuring the long-term self-renewal of human embryonic stem cells are still only partly understood, limiting their use in cellular therapies. Here we found that increased activity of the RB cell cycle inhibitor in human embryonic stem cells induces cell cycle arrest, differentiation and cell death. Conversely, inactivation of the entire RB family (RB, p107 and p130) in human embryonic stem cells triggers G2/M arrest and cell death through functional activation of the p53 pathway and the cell cycle inhibitor p21. Differences in E2F target gene activation upon loss of RB family function between human embryonic stem cells, mouse embryonic stem cells and human fibroblasts underscore key differences in the cell cycle regulatory networks of human embryonic stem cells. Finally, loss of RB family function promotes genomic instability in both human and mouse embryonic stem cells, uncoupling cell cycle defects from chromosomal instability. These experiments indicate that a homeostatic level of RB activity is essential for the self-renewal and the survival of human embryonic stem cells.

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“…Treatment of hESCs with the E2F inhibitor HLM006474 (ref. 28) significantly decreased hESC proliferation (Fig. 2d) and led to an increase in cell death (Fig.…”

Section: Rb Activation In Hescs Induces Cell Cycle Arrest and Deathmentioning

confidence: 87%

The RB family is required for the self-renewal and survival of human embryonic stem cells

2012

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“…Several studies have shown the usefulness of this approach for inhibition of tumor cell growth. 49,50 Our results indicate that depleting E2F activity in a context in which the pRb and the p53 pathways are functional, which is the situation of most non-cancerous cells in an organism, renders cells susceptible to become Figure 8 Disruption of p53 in E2F1/E2F2 mutant mice promotes development of thymic lymphomas and compromises survival. (a) Life spans of WT, E2F1/E2F2 DKO, p53 − / − and E2F1/E2F2/p53 TKO mice (n = 15/genotype) analyzed using a log-rank non-parametric test and expressed as Kaplan-Meier survival curves (E2F1/E2F2 DKO versus WT, Po0.0001; E2F1/E2F2/p53 TKO versus WT, Po0.0001; E2F1/E2F2/p53 TKO versus E2F1/E2F2 DKO, Po0.0001; E2F1/E2F2/p53 TKO versus p53 − / − , Po0.0001).…”

Section: E2f-p53 Regulatory Axis In Tissue Homeostasismentioning

confidence: 93%

E2F1 and E2F2 prevent replicative stress and subsequent p53-dependent organ involution

et al. 2015

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Tissue homeostasis requires tight regulation of cellular proliferation, differentiation and apoptosis. E2F1 and E2F2 transcription factors share a critical role in tissue homeostasis, since their combined inactivation results in overall organ involution, specially affecting the pancreatic gland, which subsequently triggers diabetes. We have examined the mechanism by which these E2Fs regulate tissue homeostasis. We show that pancreas atrophy in E2F1/E2F2 double-knockout (DKO) mice is associated with mitochondrial apoptosis and activation of the p53 pathway in young animals, before the development of diabetes. A deregulated expression of E2F target genes was detected in pancreatic cells of young DKO animals, along with unscheduled DNA replication and activation of a DNA damage response. Importantly, suppression of DNA replication in vivo with aphidicolin led to a significant inhibition of the p53 pathway in DKO pancreas, implying a causal link between DNA replication stress and p53 activation in this model. We further show that activation of the p53 pathway has a key role in the aberrant phenotype of DKO mice, since targeted inactivation of p53 gene abrogated cellular apoptosis and prevented organ involution and insulin-dependent diabetes in mice lacking E2F1/E2F2. Unexpectedly, p53 inactivation unmasked oncogenic features of E2F1/E2F2-depleted cells, as evidenced by an accelerated tumor development in triple-knockout mice compared with p53 − / − mice. Collectively, our data reveal a role for E2F1 and E2F2 as suppressors of replicative stress in differentiating cells, and uncover the existence of a robust E2F-p53 regulatory axis to enable tissue homeostasis and prevent tumorigenesis. These findings have implications in the design of approaches targeting E2F for cancer therapy.

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“…A key goal in the immediate future will be to identify the consequences of RB1 inactivation that can be best exploited therapeutically to target RB1 mutant tumors. little progress has been reported on this subject, and only a few compounds have been available for research (Ma et al 2008;Sangwan et al 2012;Kurtyka et al 2014).…”

Section: The Translation Of Rb Researchmentioning

confidence: 99%

RB1: a prototype tumor suppressor and an enigma

2016

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The retinoblastoma susceptibility gene (RB1) was the first tumor suppressor gene to be molecularly defined. RB1 mutations occur in almost all familial and sporadic forms of retinoblastoma, and this gene is mutated at variable frequencies in a variety of other human cancers. Because of its early discovery, the recessive nature of RB1 mutations, and its frequency of inactivation, RB1 is often described as a prototype for the class of tumor suppressor genes. Its gene product (pRB) regulates transcription and is a negative regulator of cell proliferation. Although these general features are well established, a precise description of pRB's mechanism of action has remained elusive. Indeed, in many regards, pRB remains an enigma. This review summarizes some recent developments in pRB research and focuses on progress toward answers for the three fundamental questions that sit at the heart of the pRB literature: What does pRB do? How does the inactivation of RB change the cell? How can our knowledge of RB function be exploited to provide better treatment for cancer patients?

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A Small-Molecule E2F Inhibitor Blocks Growth in a Melanoma Culture Model

Cited by 92 publications

References 28 publications

The RB family is required for the self-renewal and survival of human embryonic stem cells

The RB family is required for the self-renewal and survival of human embryonic stem cells

E2F1 and E2F2 prevent replicative stress and subsequent p53-dependent organ involution

RB1: a prototype tumor suppressor and an enigma

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