Production of gastrointestinal tumors in mice by modulating latent TGF-β1 activation
TGF-β and its signaling pathways are important mediators in the suppression of cancers of the gastrointestinal tract. TGF-β is released from cells in a latent complex consisting of TGF-β, the TGF-β propeptide [latency associated protein (LAP)], and a latent TGF-β binding protein (LTBP). We previously generated mice in which the LTBP-binding cysteine residues in LAP TGF-β1 were mutated to serine precluding covalent interactions with LTBP. These Tgfb1(C33S/C33S) mice develop multiorgan inflammation and tumors consistent with reduced TGF-β1 activity. To test whether further reduction in active TGF-β levels would yield additional tumors and a phenotype more similar to Tgfb1(-/-) mice, we generated mice that express TGF-β1(C33S) and are deficient in either integrin β8 or TSP-1, known activators of latent TGF-β1. In addition, we generated mice that have one mutant allele and one null allele at the Tgfb1 locus, reasoning that these mice should synthesize half the total amount of TGF-β1 as Tgfb1(C33S/C33S) mice, and the amount of active TGF-β1 would be correspondingly decreased compared with Tgfb1(C33S/C33S) mice. These compound-mutant mice displayed more severe inflammation and higher tumor numbers than the parental Tgfb1(C33S/C33S) animals. The level of active TGF-β1 in compound mutant mice seemed to be decreased compared with Tgfb1(C33S/C33S) mice as determined from analyses of surrogate markers of active TGF-β, such as P-Smad2, C-Myc, KI-67, and markers of cell-cycle traverse. We conclude that these mutant mice provide a useful system for modulating TGF-β levels in a manner that determines tumor number and inflammation within the gastrointestinal tract.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2013 |
|---|---|
| Erschienen: |
2013 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:73 |
|---|---|
| Enthalten in: |
Cancer research - 73(2013), 1 vom: 01. Jan., Seite 459-68 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Shibahara, Kotaro [VerfasserIn] |
|---|
| Links: |
|---|
| Themen: |
Journal Article |
|---|
| Anmerkungen: |
Date Completed 27.02.2013 Date Revised 21.10.2021 published: Print-Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1158/0008-5472.CAN-12-3141 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM222294477 |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM222294477 | ||
| 003 | DE-627 | ||
| 005 | 20231224053936.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231224s2013 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1158/0008-5472.CAN-12-3141 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n0741.xml |
| 035 | |a (DE-627)NLM222294477 | ||
| 035 | |a (NLM)23117884 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Shibahara, Kotaro |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Production of gastrointestinal tumors in mice by modulating latent TGF-β1 activation |
| 264 | 1 | |c 2013 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 27.02.2013 | ||
| 500 | |a Date Revised 21.10.2021 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a TGF-β and its signaling pathways are important mediators in the suppression of cancers of the gastrointestinal tract. TGF-β is released from cells in a latent complex consisting of TGF-β, the TGF-β propeptide [latency associated protein (LAP)], and a latent TGF-β binding protein (LTBP). We previously generated mice in which the LTBP-binding cysteine residues in LAP TGF-β1 were mutated to serine precluding covalent interactions with LTBP. These Tgfb1(C33S/C33S) mice develop multiorgan inflammation and tumors consistent with reduced TGF-β1 activity. To test whether further reduction in active TGF-β levels would yield additional tumors and a phenotype more similar to Tgfb1(-/-) mice, we generated mice that express TGF-β1(C33S) and are deficient in either integrin β8 or TSP-1, known activators of latent TGF-β1. In addition, we generated mice that have one mutant allele and one null allele at the Tgfb1 locus, reasoning that these mice should synthesize half the total amount of TGF-β1 as Tgfb1(C33S/C33S) mice, and the amount of active TGF-β1 would be correspondingly decreased compared with Tgfb1(C33S/C33S) mice. These compound-mutant mice displayed more severe inflammation and higher tumor numbers than the parental Tgfb1(C33S/C33S) animals. The level of active TGF-β1 in compound mutant mice seemed to be decreased compared with Tgfb1(C33S/C33S) mice as determined from analyses of surrogate markers of active TGF-β, such as P-Smad2, C-Myc, KI-67, and markers of cell-cycle traverse. We conclude that these mutant mice provide a useful system for modulating TGF-β levels in a manner that determines tumor number and inflammation within the gastrointestinal tract | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 7 | |a Transforming Growth Factor beta1 |2 NLM | |
| 700 | 1 | |a Ota, Mitsuhiko |e verfasserin |4 aut | |
| 700 | 1 | |a Horiguchi, Masahito |e verfasserin |4 aut | |
| 700 | 1 | |a Yoshinaga, Keiji |e verfasserin |4 aut | |
| 700 | 1 | |a Melamed, Jonathan |e verfasserin |4 aut | |
| 700 | 1 | |a Rifkin, Daniel B |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Cancer research |d 1945 |g 73(2013), 1 vom: 01. Jan., Seite 459-68 |w (DE-627)NLM000001740 |x 1538-7445 |7 nnns |
| 773 | 1 | 8 | |g volume:73 |g year:2013 |g number:1 |g day:01 |g month:01 |g pages:459-68 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1158/0008-5472.CAN-12-3141 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 73 |j 2013 |e 1 |b 01 |c 01 |h 459-68 | ||