A genetic screen identifies PITX1 as a suppressor of RAS activity and tumorigenicity (Cell, 121:849-858, 17 June 2005)

報告日期: 2005/10/28
報告時間: 17:10/18:00
報告學生: 陳彥任
講評老師: 劉校生
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A genetic screen identifies PITX1 as a suppressor of Ras activity and tumorigenicity

Cell 121, 849-858 (2005)

Speaker陳彥任                                                                                                                                 Time2005/10/28 17:10-18:00

Commentator劉校生 老師                            Room602

Abstract

  Human tumors harbor multiple genetic alterations in genes controlling cell growth, differentiation, and survival. These genetic changes include activation of oncogenes and inactivation of tumor-suppressor genes. The Ras gene family is one of the most frequently avtivated oncogenes in human cancers, indicating that Ras activation is important for tumorigenesis. However, a large propotion of these cancers still retain wild-type Ras alleles, suggesting that either the Ras pathway is activated in a distinct manner or another pathway is deregulated. In this paper, the authors used an RNA interference (RNAi) library combined with soft agar assay to screen for novel tumor suppressor genes that inhibits the activity of oncogenic Ras . By this approach, they identified a knockdown construct targeting the homeodomain pituitary transcription factor PITX1 with a transforming activity comparable to oncogenic Ras overexpression. In order to determine the tumor inhibitory role of PITX1 in human cancers, the authors observed that suppression of PITX1 expression activates the Ras pathway and causes the same phenotype as oncogenic Ras overexpression. Moreover, they also observed that lower expression of PITX1 in prostate and bladder cancers and in colon cancer cell lines containing wild-type Ras. Re-expression of PITX1 in the colon cancer cell inhibited cell proliferation and tumorigenicity in a wild-type Ras dependent manner. Finally, they also found that RASAL1, a Ras-GTPase-activating protein, is a transcription target of PITX1. In conclusion, PITX1 is a novel tumor suppressor gene and suppresses the Ras activity and tumorigenicity through RASAL1.

 

References:

1.      Voorhoeve and Agami Cancer Cell 4, 311-319 (2002)

2.      Berns, et al. Nature 428,431-437 (2004)