Skp2 targeting suppresses tumorienesis by Arf-p53-independent cellular senescence (Nature, 2010, 464:374-379)

報告日期: 2010/10/22
報告時間: 17:10/18:00
報告學生: 莊博凱
講評老師: 蔣輯武
附件下載:

Full text: http://basicmed.med.ncku.edu.tw/admin/up_img/991022-3.pdf

Skp2 targeting suppresses tumorigenesis by Arf-p53-independent cellular senescence

Nature. 2010 Jul 15;466(7304):398

 

Speaker : Po-Kai Chuang(莊博凱)

Commentator : Chi-Wu Chiang, Ph.D(蔣輯武)

Date : 17:00-18:00, Oct 22, 2010

Place : Room 602

 

Abstract:

Cell senescence, a natural antitumor program in response to stress that lead into immortal growth arrest, is an attractive therapeutic concept of against the progression of malignant tumor. Recent evidence suggests that oncogene-induced senescence can be triggered by multiple pathways involved and targeting specific tumor suppressors (such of ARF–p53 pathway or p16INK4a). However, the ubiquitin ligase SKP2, which is part of the SKP1–CUL1–F-box (SCF) complex, has been implicated in tumorigenesis of initiation procession to degrade the tumour suppressor p27 to get over-proliferative potential. Conversely, loss of SKP2 expression display features of cellular senescence inhibited oncogenic activation through expression of p27 by ARF–p53 pathway independent.

Hence, theirs results indicate that mouse embryonic fibroblasts (MEFs) derived from Skp2-/- embryos are not facile to rise E1A and Ras expression resulted in senescence in vitro determined by the absence of β-galactosidase expression. To eliminate ARFp53 pathway can trigger senescence by loss function of the tumour suppressor PTEN in Skp2-/- MEFs. In contrast, the p27, p21 and the ER stress response protein ATF4, are presented in Skp2-/-;Pten+/- and Skp2-/-;Arf-/- MEFs that induced senescence to reply to oncogene activation. Additionally, knock down of p27, p21 and ATF4 expression using RNA interference in the absence of SKP2 of senescence. Pten+/- mice and Skp2-/-;Pten+/- mice showed increased expression of p27 by staining of lymph nodes. Specifically, Skp2-/-;Arf-/- mice reduced prostate cancer growth, which occur in around 33% of Arf-null mice and were decreased in Skp2-/- Pten+/- mice. Inclusive of  p27 expression was increased in prostate cancer from these mice and correlated with β-galactosidase expression over 15 months.

The therapeutic implications of these results were shown inhibition of SKP2–SCF complex activity by using a drug MLN4924 that was suppressed the PTEN- and TP53-null human prostate cancer cell line PC3 in vitro and in xenografts. Notably, these findings offer new approaches in inactivation of SKP2-mediated senescence for cancer therapy.

 

Reference

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