 | ANTICANCER MOLECULES: STRUCTURE, FUNCTION, AND DESIGN
Copyright © 1999 by the New York Academy of Sciences
description
Annals of the New York Academy of Sciences 886:73-82 (1999)
© 1999 New York Academy of Sciences
Intracellular Signaling of the TGF-ß Superfamily by Smad Proteins
MASAHIRO KAWABATAa,
TAKESHI IMAMURA,
HIROFUMI INOUE,
JUN-ICHI HANAI,
AYAKO NISHIHARA,
AKI HANYU,
MASAO TAKASE,
YASUHIRO ISHIDOU,
YOSHIYUKI UDAGAWA,
EIICHI OEDA,
DAISUKE GOTO,
KEN YAGI,
MITSUYASU KATO AND
KOHEI MIYAZONO
Department of Biochemistry, The Cancer Institute, Japanese Foundation for Cancer Research (JFCR), and Research for the Future Program, Japan Society for the Promotion of Science, 1-37-1 Kami-ikebukuro, Toshima-ku, Tokyo 170-8455, Japan
aPhone, japan-3-3918-0342; fax Japan-3-3918-0342.
e-mail, mkawabat-ind{at}umin.u-tokyo.ac.jp
TGF-ß is a potent inhibitor of cell growth, and accumulating evidence suggests that perturbation of the TGF-ß signaling pathway leads to tumorigenesis. Smads are recently identified proteins that mediate intracellular signaling of the TGF-ß superfamily. Smads 2 and 3 are phosphorylated by the TGF-ß type I receptor. Smad4 was originally identified as a candidate tumor suppressor gene in pancreatic cancers. Smads 2 and 3 form complexes with Smad4 upon TGF-ß stimulation. The heteromeric Smad complexes translocate into the nucleus, where they activate expression of target genes. Our recent study demonstrated that Smads exist as monomers in the absence of TGF-ß. Smads 2 and 3 form homo- as well as hetero-oligomers with Smad4 upon ligand stimulation. Both homo-oligomers and hetero-oligomers directly bind to DNA, suggesting that the signaling pathway of Smads may be multiplex. Smads 2 and 3 associate with transcriptional coactivators such as p300 in a ligand-dependent manner. p300 enhances transactivation by TGF-ß, suggesting that coactivators link Smads to the basal transcriptional machinery. A missense mutation of Smad2 identified in colorectal and lung cancers was introduced to Smad3. The mutant, Smad3(DE), blocked the activation of wild-type Smad2 and Smad3. Thus, the missense mutation not only disrupts the function of the wild-type Smad but also creates a dominant-negative Smad, which could actively contribute to oncogenesis.
This article has been cited by other articles:
|
|
|
|
 
Y.-G. Chen, Q. Wang, S.-L. Lin, C. D. Chang, J. Chung, and S.-Y. Ying
Activin Signaling and Its Role in Regulation of Cell Proliferation, Apoptosis, and Carcinogenesis.
Experimental Biology and Medicine,
May 1, 2006;
231(5):
534 - 544.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T M Lovell, P G Knight, and R T Gladwell
Differential expression of mRNAs encoding the putative inhibin co-receptor (betaglycan) and activin type-I and type-II receptors in preovulatory and prehierarchical follicles of the laying hen ovary
J. Endocrinol.,
February 1, 2006;
188(2):
241 - 249.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Suzuki, G.-i. Kusakai, Y. Shimojo, J. Chen, T. Ogura, M. Kobayashi, and H. Esumi
Involvement of Transforming Growth Factor-{beta}1 Signaling in Hypoxia-induced Tolerance to Glucose Starvation
J. Biol. Chem.,
September 9, 2005;
280(36):
31557 - 31563.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
I.-M. Kim, S. Ramakrishna, G. A. Gusarova, H. M. Yoder, R. H. Costa, and V. V. Kalinichenko
The Forkhead Box M1 Transcription Factor Is Essential for Embryonic Development of Pulmonary Vasculature
J. Biol. Chem.,
June 10, 2005;
280(23):
22278 - 22286.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M.F. Termaat, F.C. Den Boer, F.C. Bakker, P. Patka, and H.J.Th.M. Haarman
Bone Morphogenetic Proteins. Development and Clinical Efficacy in the Treatment of Fractures and Bone Defects
J. Bone Joint Surg. Am.,
June 1, 2005;
87(6):
1367 - 1378.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L L Burger, D J Haisenleder, A C Dalkin, and J C Marshall
Regulation of gonadotropin subunit gene transcription
J. Mol. Endocrinol.,
December 1, 2004;
33(3):
559 - 584.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Chiba, K. Takeshita, Y. Imai, K. Kumano, M. Kurokawa, S. Masuda, K. Shimizu, S. Nakamura, F. H. Ruddle, and H. Hirai
Homeoprotein DLX-1 interacts with Smad4 and blocks a signaling pathway from activin A in hematopoietic cells
PNAS,
December 23, 2003;
100(26):
15577 - 15582.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
I.-J. Kim, H. N. Beck, P. J. Lein, and D. Higgins
Interferon gamma Induces Retrograde Dendritic Retraction and Inhibits Synapse Formation
J. Neurosci.,
June 1, 2002;
22(11):
4530 - 4539.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. A. MacConell, A. M. O. Leal, and W. W. Vale
The Distribution of Betaglycan Protein and mRNA in Rat Brain, Pituitary, and Gonads: Implications for a Role for Betaglycan in Inhibin-Mediated Reproductive Functions
Endocrinology,
March 1, 2002;
143(3):
1066 - 1075.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y. Zhou, F. G. Gwadry, W. C. Reinhold, L. D. Miller, L. H. Smith, U. Scherf, E. T. Liu, K. W. Kohn, Y. Pommier, and J. N. Weinstein
Transcriptional Regulation of Mitotic Genes by Camptothecin-induced DNA Damage: Microarray Analysis of Dose- and Time-dependent Effects
Cancer Res.,
March 1, 2002;
62(6):
1688 - 1695.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Maitra, K. Molberg, J. Albores-Saavedra, and G. Lindberg
Loss of Dpc4 Expression in Colonic Adenocarcinomas Correlates with the Presence of Metastatic Disease
Am. J. Pathol.,
October 1, 2000;
157(4):
1105 - 1111.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
