Differential p53-independent outcomes of p19(Arf) loss in oncogenesis.
Differential p53-independent outcomes of p19(Arf) loss in oncogenesis.
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DOI：
10.1126/scisignal.2000053
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发表时间：
2009-08-18
影响因子：
7.3
通讯作者：
Pandolfi PP
中科院分区：
文献类型：
--
作者：
Chen Z;Carracedo A;Lin HK;Koutcher JA;Behrendt N;Egia A;Alimonti A;Carver BS;Gerald W;Teruya-Feldstein J;Loda M;Pandolfi PP
据报道，肿瘤抑制因子p19Arf的一个功能是稳定p53，在对致癌损伤的反应中提供一个关键的检查点。Pten的急性缺失导致p19Arf、p53和p21蛋白丰度的增加，这是失效安全衰老反应的一部分。在这里，我们报道前列腺上皮中p19Arf的缺失不会加速-而是部分抑制- pten缺陷小鼠的前列腺癌表型。此外，在Pten-p19Arf双突变小鼠的前列腺中观察到细胞衰老和癌前腺体数量的进一步减少。在前列腺上皮和原代小鼠胚胎成纤维细胞（MEFs）中，Pten缺失后p53蛋白丰度的增加不受p19Arf同时缺失的影响。然而，与前列腺上皮相比，在缺乏Pten的mef中，p19Arf的缺乏消除了细胞衰老，促进了细胞的过度增殖和转化，尽管p53的丰度没有减弱。与PTEN缺陷小鼠前列腺中p19Arf丢失的影响一致，我们发现在人类前列腺癌中，PTEN的丢失与p14ARF（人类相当于小鼠p19Arf）的丢失无关。总的来说，这些数据揭示了p19Arf失活在前列腺癌和mef中独立于p53途径的Pten丢失的不同后果。
One reported function of the tumor suppressor p19Arf is to stabilize p53, providing a critical checkpoint in the response to oncogenic insults. Acute loss of Pten leads to an increase in the abundance of p19Arf, p53, and p21 proteins as part of a fail-safe senescence response. Here, we report that loss of p19Arf in prostate epithelium does not accelerate—but rather partially inhibits—the prostate cancer phenotype of Pten-deficient mice. Moreover, cellular senescence and a further decrease in the number of pre-neoplastic glands were observed in prostates of the Pten-p19Arf double-mutant mice. In both prostate epithelium and primary mouse embryo fibroblasts (MEFs), the increase in p53 protein abundance found upon loss of Pten was unaffected by the simultaneous loss of p19Arf. However, in contrast to that in the prostate epithelium, p19Arf deficiency in MEFs lacking Pten abolished cell senescence and promoted hyperproliferation and transformation despite the unabated increase in p53 abundance. Consistent with the effect of p19Arf loss in Pten-deficient mouse prostate, we found that in human prostate cancers, loss of PTEN was not associated with loss of p14ARF (the human equivalent of mouse p19Arf). Collectively, these data reveal differential consequences of p19Arf inactivation in prostate cancer and MEFs upon Pten loss that are independent of the p53 pathway.
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影响因子：
64.8
作者：
Song, Min Sup;Salmena, Leonardo;Carracedo, Arkaitz;Egia, Ainara;Lo-Coco, Francesco;Teruya-Feldstein, Julie;Pandolfi, Pier Paolo
通讯作者：
Pandolfi, Pier Paolo
影响因子：
8
作者：
Asano, T;Yao, YX;Reddy, SAG
通讯作者：
Reddy, SAG
影响因子：
11.4
作者：
Stott, FJ;Bates, S;Peters, G
通讯作者：
Peters, G
DOI：
10.1159/000139878
发表时间：
2008-01-01
期刊：
CONTROVERSIES IN THE TREATMENT OF PROSTATE CANCER
影响因子：
--
作者：
Schostak, M.;Miller, K.;Schrader, M.
通讯作者：
Schrader, M.
影响因子：
30.8
作者：
Eeles, Rosalind A.;Kote-Jarai, Zsofia;Easton, Douglas F.
通讯作者：
Easton, Douglas F.