| Creator |
|
|---|
| Abstract |
- RAS and Rho small GTPases are key molecular switches that control cell dynamics, cell
growth and tissue development through their distinct signaling pathways. While much has been
learnt about their individual functions in both cell and animal models, the physiological and
pathophysiological consequences of their signaling crosstalk in multi-cellular context in vivo
remain largely unknown, especially in liver development and liver tumorigenesis. Furthermore,
the roles of RhoA in RAS-mediated transformation and their crosstalk in vitro remain highly
controversial. When challenged with carcinogens, zebrafish developed liver cancer that
resembles the human liver cancer both molecularly and histopathologically. Capitalizing on the
growing importance and relevance of zebrafish (Danio rerio) as an alternate cancer model, we
have generated liver-specific, Tet-on inducible transgenic lines expressing oncogenic Kras[superscript G12V],
RhoA, constitutively-active RhoA[superscript G14V] or dominant-negative RhoA[superscript T19N]. Double transgenic lines
expressing Kras[superscript G12V] with one of the three RhoA genes were also generated. Based on
quantitative bioimaging and molecular markers for genetic and signaling aberrations, we showed
that the induced expression of oncogenic Kras during early development led to liver enlargement
and hepatocyte proliferation, associated with elevated Erk phosphorylation, Akt2-p21Cip
expression and activation. Such an increase in liver size and Akt2 expression was augmented
by dominant-negative RhoA[superscript T19N], but was abrogated by the constitutive-active RhoA[superscript G14V].
Consequently, induced expression of the oncogenic Kras in adult transgenic fish led to the
development of hepatocellular carcinomas. Survival studies further revealed that the co-expression
of dominant-negative RhoA[superscript T19N] with oncogenic Kras increased the mortality rate
compared to the other single or double transgenic lines. This study represents the first in
vivo investigation of the previously unappreciated signaling crosstalk between Kras and RhoA in
regulating liver overgrowth and liver tumorigenesis. Our results also implicate that activating
Rho could be beneficial to suppress the Kras-induced liver malignancies.
|
|---|
| Resource Type |
|
|---|
| DOI |
|
|---|
| Date Available |
|
|---|
| Date Issued |
|
|---|
| Citation |
- Chew, T. W., Liu, X. J., Liu, L., Spitsbergen, J. M., Gong, Z., & Low, B. C. (2014). Crosstalk of Ras and Rho: activation of RhoA abates Kras-induced liver tumorigenesis in transgenic zebrafish models. Oncogene, 33(21), 2717-2727. doi:10.1038/onc.2013.240
|
|---|
| Journal Title |
|
|---|
| Journal Volume |
|
|---|
| Journal Issue/Number |
|
|---|
| Keyword |
|
|---|
| Rights Statement |
|
|---|
| Funding Statement (additional comments about funding) |
- This work was supported by the NUS graduate research scholarship awarded to TW Chew and inpart by grants from the Biomedical Research Council of Singapore (ZYG, BCL), NationalMedical Research Council (ZYG, BCL), and the Mechanobiology Institute of Singapore (BCL)which is co-funded through the National Research Foundation and the Ministry of Education,Singapore.
|
|---|
| Publisher |
|
|---|
| Peer Reviewed |
|
|---|
| Language |
|
|---|
| Replaces |
|
|---|
| Additional Information |
- description.provenance : Approved for entry into archive by Deanne Bruner(deanne.bruner@oregonstate.edu) on 2014-09-12T18:47:20Z (GMT) No. of bitstreams: 8
SpitsbergenJanMicrobiologyCrosstalkRasRho.pdf: 2630175 bytes, checksum: 389fcb260580df769677a407435bd463 (MD5)
SpitsbergenJanMicrobiologyCrosstalkRasRho(SupplementaryFigure1).pdf: 143798 bytes, checksum: 6dbcb515effd8bc2f1c8c15d565adca6 (MD5)
SpitsbergenJanMicrobiologyCrosstalkRasRho(SupplementaryFigure2).pdf: 107274 bytes, checksum: c7df61130043672940dffa05f9f31e4e (MD5)
SpitsbergenJanMicrobiologyCrosstalkRasRho(SupplementaryFigure3).pdf: 113618 bytes, checksum: 08f2f5f151ae4aaa76a6c71906ea6953 (MD5)
SpitsbergenJanMicrobiologyCrosstalkRasRho(SupplementaryFigure4).pdf: 181570 bytes, checksum: 073620d30ed00ebf1165f307e363f58b (MD5)
SpitsbergenJanMicrobiologyCrosstalkRasRho(SupplementaryFigure5).pdf: 50375 bytes, checksum: 3b366b2edf6bd7a83c8288e89729b2fb (MD5)
SpitsbergenJanMicrobiologyCrosstalkRasRho(SupplementaryTable1).pdf: 36965 bytes, checksum: 1c6083b2608a276e30546e75745f3961 (MD5)
SpitsbergenJanMicrobiologyCrosstalkRasRho(SupplementaryTable2).pdf: 54549 bytes, checksum: 1f4e017f26569e6b174a85800f733f67 (MD5)
- description.provenance : Submitted by Deanne Bruner (deanne.bruner@oregonstate.edu) on 2014-09-12T18:46:23Z
No. of bitstreams: 8
SpitsbergenJanMicrobiologyCrosstalkRasRho.pdf: 2630175 bytes, checksum: 389fcb260580df769677a407435bd463 (MD5)
SpitsbergenJanMicrobiologyCrosstalkRasRho(SupplementaryFigure1).pdf: 143798 bytes, checksum: 6dbcb515effd8bc2f1c8c15d565adca6 (MD5)
SpitsbergenJanMicrobiologyCrosstalkRasRho(SupplementaryFigure2).pdf: 107274 bytes, checksum: c7df61130043672940dffa05f9f31e4e (MD5)
SpitsbergenJanMicrobiologyCrosstalkRasRho(SupplementaryFigure3).pdf: 113618 bytes, checksum: 08f2f5f151ae4aaa76a6c71906ea6953 (MD5)
SpitsbergenJanMicrobiologyCrosstalkRasRho(SupplementaryFigure4).pdf: 181570 bytes, checksum: 073620d30ed00ebf1165f307e363f58b (MD5)
SpitsbergenJanMicrobiologyCrosstalkRasRho(SupplementaryFigure5).pdf: 50375 bytes, checksum: 3b366b2edf6bd7a83c8288e89729b2fb (MD5)
SpitsbergenJanMicrobiologyCrosstalkRasRho(SupplementaryTable1).pdf: 36965 bytes, checksum: 1c6083b2608a276e30546e75745f3961 (MD5)
SpitsbergenJanMicrobiologyCrosstalkRasRho(SupplementaryTable2).pdf: 54549 bytes, checksum: 1f4e017f26569e6b174a85800f733f67 (MD5)
- description.provenance : Made available in DSpace on 2014-09-12T18:47:20Z (GMT). No. of bitstreams: 8
SpitsbergenJanMicrobiologyCrosstalkRasRho.pdf: 2630175 bytes, checksum: 389fcb260580df769677a407435bd463 (MD5)
SpitsbergenJanMicrobiologyCrosstalkRasRho(SupplementaryFigure1).pdf: 143798 bytes, checksum: 6dbcb515effd8bc2f1c8c15d565adca6 (MD5)
SpitsbergenJanMicrobiologyCrosstalkRasRho(SupplementaryFigure2).pdf: 107274 bytes, checksum: c7df61130043672940dffa05f9f31e4e (MD5)
SpitsbergenJanMicrobiologyCrosstalkRasRho(SupplementaryFigure3).pdf: 113618 bytes, checksum: 08f2f5f151ae4aaa76a6c71906ea6953 (MD5)
SpitsbergenJanMicrobiologyCrosstalkRasRho(SupplementaryFigure4).pdf: 181570 bytes, checksum: 073620d30ed00ebf1165f307e363f58b (MD5)
SpitsbergenJanMicrobiologyCrosstalkRasRho(SupplementaryFigure5).pdf: 50375 bytes, checksum: 3b366b2edf6bd7a83c8288e89729b2fb (MD5)
SpitsbergenJanMicrobiologyCrosstalkRasRho(SupplementaryTable1).pdf: 36965 bytes, checksum: 1c6083b2608a276e30546e75745f3961 (MD5)
SpitsbergenJanMicrobiologyCrosstalkRasRho(SupplementaryTable2).pdf: 54549 bytes, checksum: 1f4e017f26569e6b174a85800f733f67 (MD5)
Previous issue date: 2014-05-22
|
|---|