p53 and E2f: partners in life and death

Polager, Shirley; Ginsberg, Doron

doi:10.1038/nrc2718

Cited by 435 publications

(453 citation statements)

References 128 publications

Supporting

Mentioning

426

Contrasting

Unclassified

Order By: Relevance

“…Ablation of Bax or over‐expression of the anti‐apoptotic factors (Bcl‐2 or Bcl‐X L ) result in disruption of spermatogenesis because of eliminated first‐wave apoptosis. Interestingly, E2F1 has been shown to regulate these factors either directly or via p53 (reviewed in (Polager & Ginsberg, 2009)). An absence of E2F1‐mediated activation of these genes is a possible cause of the decreased first‐wave apoptosis of spermatogonia in the E2F1 −/− testes.…”

Section: Discussionmentioning

confidence: 99%

E2F1 controls germ cell apoptosis during the first wave of spermatogenesis

et al. 2015

View full text Add to dashboard Cite

SummaryCell cycle control during spermatogenesis is a highly complex process owing to the control of the mitotic expansion of the spermatogonial cell population and following meiosis, induction of DNA breaks during meiosis and the high levels of physiological germ‐cell apoptosis. We set out to study how E2F1, a key controller of cell cycle, apoptosis, and DNA damage responses, functions in the developing and adult testis. We first analyzed the expression pattern of E2f1 during post‐natal testis development using RNA in situ hybridization, which showed a differential expression pattern of E2f1 in the adult and juvenile mouse testes. To study the function of E2f1, we took advantage of the E2F1−/− mouse line, which was back‐crossed to C57Bl/6J genetic background. E2f1 loss led to a severe progressive testicular atrophy beginning at the age of 20 days. Spermatogonial apoptosis during the first wave of spermatogenesis was decreased. However, already in the first wave of spermatogenesis an extensive apoptosis of spermatocytes was observed. In the adult E2F1−/− testes, the atrophy due to loss of spermatocytes was further exacerbated by loss of spermatogonial stem cells. Surprisingly, only subtle changes in global gene expression array profiling were observed in E2F1−/− testis at PND20. To dissect the changes in each testicular cell type, an additional comparative analysis of the array data was performed making use of previously published data on transcriptomes of the individual testicular cell types. Taken together, our data indicate that E2F1 has a differential role during first wave of spermatogenesis and in the adult testis, which emphasizes the complex nature of cell cycle control in the developing testis.

show abstract

Section: Discussionmentioning

confidence: 99%

E2F1 controls germ cell apoptosis during the first wave of spermatogenesis

et al. 2015

View full text Add to dashboard Cite

show abstract

“…E2F1 is a transcription factor involved in cell-cycle control and apoptosis, whose expression is often dysregulated in human tumors. 32,33 Upon DNA damage, E2F1 is phosphorylated by CHK1 and CHK2 and subsequently induces transcription of p73 and its target genes to initiate p53-independent apoptosis. 34 Studies on murine embryonic fibroblasts indicated that the AHR inhibits E2F1-induced apoptosis, probably due to a physical interaction of both transcription factors.…”

Section: Discussionmentioning

confidence: 99%

Evidence for a novel anti-apoptotic pathway in human keratinocytes involving the aryl hydrocarbon receptor, E2F1, and checkpoint kinase 1

et al. 2013

View full text Add to dashboard Cite

Exposure of keratinocytes (KC) to ultraviolet (UV) radiation results in the initiation of apoptosis, a protective mechanism that eliminates cells harboring irreparable DNA damage. Hence, a manipulation of UV-induced apoptosis may significantly influence photocarcinogenesis. We have discovered that the aryl hydrocarbon receptor (AHR), a key regulator of drug metabolism and an UVB-sensitive transcription factor, serves an anti-apoptotic function in UVB-irradiated human KC. Chemical and shRNA-mediated inhibition of AHR signaling sensitized KC to UVB-induced apoptosis by decreasing the expression of E2F1 and its target gene checkpoint kinase 1 (CHK1). The decreased expression of these cell-cycle regulators was due to an enhanced expression of p27 KIP1 and an associated decrease in phosphorylation of both cyclin-dependent kinase 2 and its substrate molecule retinoblastoma protein. The subsequent inhibition of E2F1 autoregulation and downstream CHK1 expression resulted in an enhanced susceptibility of damaged cells to undergo apoptosis. Accordingly, ectopic overexpression of either E2F1 or CHK1 in AHR-knockdown KC attenuated the observed sensitization to UVB-induced apoptosis. Using an AHR-knockout SKH-1 hairless mouse model, we next demonstrated the physiological relevance of the anti-apoptotic function of AHR. In contrast to their AHR-proficient littermates, the constitutive expression of E2F1 and CHK1 was significantly reduced in the skin of AHR-knockout mice. Accordingly, a single exposure of the animals to UVB resulted in an enhanced cleavage of caspase-3 in the skin of AHR-knockout mice. These results identify for the first time the AHR-E2F1-CHK1 axis as a novel anti-apoptotic pathway in KC, which may represent a suitable target for chemoprevention of non-melanoma skin cancer. With an annual incidence of two to three million new cases worldwide, non-melanoma skin cancer (NMSC) is one of the most frequent forms of cancer in humans (World Health Organization; http://www.who.int/uv/faq/skincancer/en/index1 .html). Typically, NMSCs, such as basal cell and squamous cell carcinomas, occur on sun-exposed areas of the skin, indicating that solar ultraviolet (UV) radiation, especially its UVB part (290-320 nm), is the most important etiological factor. 1,2 In fact, it is well established that UVB radiation gives rise to skin cancer without additional initiators or promoters and thus is a complete carcinogen. 1 Because of the thinning of the ozone layer, the increase in recreational sunbathing and the enhanced usage of UV tanning beds, the incidence of NMSC is expected to increase in future years, 1,2 underscoring the urgent need for novel preventives against UV-induced skin malignancies.When skin is exposed to solar radiation, high-energy UVB photons penetrate into the epidermis and initiate the so-called UVB response. 3 The main trigger of this stress response is the absorbance of UVB rays by DNA, which leads to the generation of highly mutagenic DNA photoproducts. 3,4 In addition, UVB exposure results in the formation...

show abstract

“…Transcriptional pathways known to modulate levels of the Bcl-2 protein family (including that of Noxa) involve p53 or E2F-1. 25,26 E2F-1 differs from that of other E2F family members due to its ability to regulate not only cell-cycle progression but also apoptosis as it directly induces the expression of p73, of caspase 3 and 7 and of some pro-apoptotic Bcl-2 family members. [27][28][29][30][31][32][33][34] We show here that E2F-1 is a major contributor of caspase-dependent induction of Noxa in response to ABT-737 treatment.…”

mentioning

confidence: 99%

pRb/E2F-1-mediated caspase-dependent induction of Noxa amplifies the apoptotic effects of the Bcl-2/Bcl-xL inhibitor ABT-737

et al. 2013

View full text Add to dashboard Cite

Although Bcl-2 family members control caspase activity by regulating mitochondrial permeability, caspases can, in turn, amplify the apoptotic process upstream of mitochondria by ill-characterized mechanisms. We herein show that treatment with a potent inhibitor of Bcl-2 and Bcl-xL, ABT-737, triggers caspase-dependent induction of the BH3-only protein, Mcl-1 inhibitor, Noxa. RNA interference experiments reveal that induction of Noxa, and subsequent cell death, rely not only on the transcription factor E2F-1 but also on its regulator pRb. In response to ABT-737, pRb is cleaved by caspases into a p68Rb form that still interacts with E2F-1. Moreover, pRb occupies the noxa promoter together with E2F-1, in a caspase-dependent manner upon ABT-737 treatment. Thus, caspases contribute to trigger the mitochondrial apoptotic pathway by coupling Bcl-2/Bcl-xL inhibition to that of Mcl-1, via the pRb/E2F-1-dependent induction of Noxa.

show abstract

p53 and E2f: partners in life and death

Cited by 435 publications

References 128 publications

E2F1 controls germ cell apoptosis during the first wave of spermatogenesis

E2F1 controls germ cell apoptosis during the first wave of spermatogenesis

Evidence for a novel anti-apoptotic pathway in human keratinocytes involving the aryl hydrocarbon receptor, E2F1, and checkpoint kinase 1

pRb/E2F-1-mediated caspase-dependent induction of Noxa amplifies the apoptotic effects of the Bcl-2/Bcl-xL inhibitor ABT-737

Contact Info

Product

Resources

About