Reference SummaryMyant KB, Cell Stem Cell 2013 Jun 6;12(6):761-73

Title

ROS Production and NF-kappaB Activation Triggered by RAC1 Facilitate WNT-Driven Intestinal Stem Cell Proliferation and Colorectal Cancer Initiation.

Authors

Myant KB; Cammareri P; McGhee EJ; Ridgway RA; Huels DJ; Cordero JB; Schwitalla S; Kalna G; Ogg EL; Athineos D; Timpson P; Vidal M; Murray GI; Greten FR; Anderson KI; Sansom OJ

Journal

Cell Stem Cell

Volume

12

Issue

6

Year

2013

Pages

761-73

Abstract

The Adenomatous Polyposis Coli (APC) gene is mutated in the majority of colorectal cancers (CRCs). Loss of APC leads to constitutively active WNT signaling, hyperproliferation, and tumorigenesis. Identification of pathways that facilitate tumorigenesis after APC loss is important for therapeutic development. Here, we show that RAC1 is a critical mediator of tumorigenesis after APC loss. We find that RAC1 is required for expansion of the LGR5 intestinal stem cell (ISC) signature, progenitor hyperproliferation, and transformation. Mechanistically, RAC1-driven ROS and NF-kappaB signaling mediate these processes. Together, these data highlight that ROS production and NF-kappaB activation triggered by RAC1 are critical events in CRC initiation.

Links

J:198485 – Mouse Genome Informatics
23665120 – National Library of Medicine/PubMed

Models

Strain Model Name Treatment Agent(s) Organ Affected Frequency Model Details
[not specified]-Apctm1Tno Lgr5tm1(cre/ERT2)Cle/+ Intestine - Large Intestine - Colon adenoma
  • tamoxifen (For inducing expression from mutant alleles)
Intestine - Large Intestine - Colon

observed

[not specified]-Apctm1Tno Lgr5tm1(cre/ERT2)Cle/+ Rac1tm1Tyb Intestine - Large Intestine - Colon adenoma
  • tamoxifen (For inducing expression from mutant alleles)
Intestine - Large Intestine - Colon

25

[not specified]-Apctm1Tno Lgr5tm1(cre/ERT2)Cle/+ Intestine - Large Intestine - Colon adenoma - microadenoma
  • tamoxifen (For inducing expression from mutant alleles)
Intestine - Large Intestine - Colon

low

[not specified]-Apctm1Tno Lgr5tm1(cre/ERT2)Cle/+ Intestine - Large Intestine - Colon foci - aberrant crypt (ACF)
  • tamoxifen (For inducing expression from mutant alleles)
Intestine - Large Intestine - Colon

low

[not specified]-Apctm1Tno Lgr5tm1(cre/ERT2)Cle/+ Rac1tm1Tyb Intestine - Large Intestine - Colon tumor
  • tamoxifen (For inducing expression from mutant alleles)
Intestine - Large Intestine - Colon

25

[not specified]-Apctm1Tno Lgr5tm1(cre/ERT2)Cle/+ Intestine adenoma
  • tamoxifen (For inducing expression from mutant alleles)
Intestine

high

[not specified]-Apctm1Tno Lgr5tm1(cre/ERT2)Cle/+ Rac1tm1Tyb Intestine adenoma
  • tamoxifen (For inducing expression from mutant alleles)
Intestine

observed

C57BL/6J-Apctm1.1Alew/+ Gt(ROSA)26Sortm1Hjf Lgr5tm1(cre/ERT2)Cle Intestine adenoma
  • tamoxifen (For inducing expression from mutant alleles)
Intestine

observed

C57BL/6J-Apctm1.1Alew/+ Gt(ROSA)26Sortm1Hjf Lgr5tm1(cre/ERT2)Cle Intestine adenoma Intestine

observed

C57BL/6J-Apctm1.1Alew/+ Gt(ROSA)26Sortm1Hjf Lgr5tm1(cre/ERT2)Cle Rac1tm1Tyb Intestine adenoma Intestine

observed

C57BL/6J-Apctm1.1Alew/+ Gt(ROSA)26Sortm1Hjf Lgr5tm1(cre/ERT2)Cle Rac1tm1Tyb Intestine adenoma
  • tamoxifen (For inducing expression from mutant alleles)
Intestine

observed

[not specified]-Apctm1Tno Lgr5tm1(cre/ERT2)Cle/+ Rac1tm1Tyb Intestine adenoma - microadenoma
  • tamoxifen (For inducing expression from mutant alleles)
Intestine

low

[not specified]-Apctm1Tno Lgr5tm1(cre/ERT2)Cle/+ Rac1tm1Tyb Intestine cyst
  • tamoxifen (For inducing expression from mutant alleles)
Intestine

low

B6;129S-Apctm1Tno Rac1tm1Tyb Tg(Vil1-cre/ERT2)23Syr Intestine hyperplasia
  • tamoxifen (For inducing expression from mutant alleles)
Intestine

observed

B6;129S-Apctm1Tno Tg(Vil1-cre/ERT2)23Syr Intestine hyperplasia
  • tamoxifen (For inducing expression from mutant alleles)
Intestine

observed

B6;129S-Rac1tm1Tyb Tg(Vil1-cre/ERT2)23Syr Intestine hyperplasia
  • tamoxifen (For inducing expression from mutant alleles)
Intestine

0

B6;129S-Tg(Vil1-cre/ERT2)23Syr Intestine hyperplasia
  • tamoxifen (For inducing expression from mutant alleles)
Intestine

0

[not specified]-Apctm1Tno Lgr5tm1(cre/ERT2)Cle/+ Rac1tm1Tyb Intestine lesion
  • tamoxifen (For inducing expression from mutant alleles)
Intestine

low

[not specified]-Apctm1Tno Lgr5tm1(cre/ERT2)Cle/+ Intestine tumor
  • tamoxifen (For inducing expression from mutant alleles)
  • N-acetyl-L-cysteine (NAC)
Intestine

observed

[not specified]-Apctm1Tno Lgr5tm1(cre/ERT2)Cle/+ Intestine tumor
  • tamoxifen (For inducing expression from mutant alleles)
Intestine

observed

[not specified]-Apctm1Tno Lgr5tm1(cre/ERT2)Cle/+ Rac1tm1Tyb Intestine tumor
  • tamoxifen (For inducing expression from mutant alleles)
Intestine

observed