E2F-1-Induced p53-independent apoptosis in transgenic mice

Holmberg, Christian; Helin, Kristian; Sehested, Maxwell; Karlström, Olle

doi:10.1038/sj.onc.1201915

Cited by 113 publications

(86 citation statements)

References 71 publications

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“…When transgenic overexpression of E2f1 was induced in the adult testis, a rapid increase in apoptosis of spermatocytes was observed and a long exposure to the transgene resulted in accumulation of GCNIS‐like cells and loss of more mature germ cells (Agger et al ., 2005). This E2f1 ‐transgene‐induced apoptosis in the testis was p53‐independent (Holmberg et al ., 1998). E2f1 has also been suggested to play a role in Sertoli cell function and cause Sertoli cell apoptosis in the absence of retinoblastoma protein (Nalam et al ., 2009).…”

Section: Introductionmentioning

confidence: 99%

E2F1 controls germ cell apoptosis during the first wave of spermatogenesis

et al. 2015

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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.

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Section: Introductionmentioning

confidence: 99%

E2F1 controls germ cell apoptosis during the first wave of spermatogenesis

et al. 2015

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“…Uncontrolled E2F1 expression may cause p53-dependent and -independent apoptosis (Hsieh et al, 1997;Phillips et al, 1997;Qin et al, 1994;Shan and Lee, 1994;Wu and Levine, 1994) and Rb can inhibit apoptosis induced by unrestrained E2F1 expression in cell cultures (Hsieh et al, 1997;Qin et al, 1994). It was previously reported that apoptosis in di erent tissues of Rb null mice could be either p53-dependent or p53-independent (Holmberg et al, 1998;Macleod et al, 1996). Analysis of Rb and E2F1 double knock-out and single knock-out mice suggested that the increased apoptosis in Rb null mice was mainly caused by the apoptotic function of E2F1 (Tsai et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

mdm2: a bridge over the two tumour suppressors, p53 and Rb

et al. 1999

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The inactivation of the p53 and Rb pathways would account for the majority of human tumours. There are many levels of cross talk between p53 and Rb that have been identi®ed. However, the identi®cation of the mdm2-Rb interaction established a closer link between the two most well studied tumour suppressors, p53 and Rb. Recent studies of the novel trimeric complex Rb-mdm2-p53 provided us with a functional insight of how the two tumour suppressors can act together in regulating p53 induced apoptosis. Beginning with the properties of the Rb-mdm2-p53 trimeric complex, we shall review the propounding evidence suggesting that the apoptotic function of p53 is linked to its transrepression function. The uncoupling of the apoptotic function and transactivation function of p53 will also be discussed.

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“…Ectopic expression of E2F1 leads to apoptosis in tissue culture cells [3][4][5] and transgenic mice. [6][7][8] Moreover, a physiological role for E2F1-mediated apoptosis is suggested by the observation that mice deficient in E2F1 have an excess of mature T cells due to a defect in thymocyte apoptosis. 9 E2F1-induced apoptosis occurs via both p53-dependent and -independent pathways.…”

Section: Introductionmentioning

confidence: 99%

Novel link between E2F and p53: proapoptotic cofactors of p53 are transcriptionally upregulated by E2F

et al. 2005

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The E2F1 transcription factor is a critical downstream target of the tumor suppressor RB. When activated, E2F1 induces cell proliferation. In addition, E2F1 can induce apoptosis via both p53-dependent and p53-independent pathways. A number of E2F-regulated genes, including ARF, ATM and Chk2, contribute to E2F-induced p53 stabilization. However, it is not known how E2F directs p53 activity towards apoptosis rather than growth arrest. We show that E2F1 upregulates the expression of four proapoptotic cofactors of p53 -ASPP1, ASPP2, JMY and TP53INP1 -through a direct transcriptional mechanism. Adenovirus E1A protein also induces upregulation of these genes, implicating endogenous E2F in this effect. TP53INP1 was shown to mediate phosphorylation of p53 on serine 46. We demonstrate that activation of E2F1 leads to phosphorylation of p53 on serine 46 and this modification is important for E2F1-p53 cooperation in apoptosis. Overall, these data provide novel functional links between RB/E2F pathway and p53-induced apoptosis.

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E2F-1-Induced p53-independent apoptosis in transgenic mice

Cited by 113 publications

References 71 publications

E2F1 controls germ cell apoptosis during the first wave of spermatogenesis

E2F1 controls germ cell apoptosis during the first wave of spermatogenesis

mdm2: a bridge over the two tumour suppressors, p53 and Rb

Novel link between E2F and p53: proapoptotic cofactors of p53 are transcriptionally upregulated by E2F

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