MH1 domain of SMAD4 binds N-terminal residues of the homeodomain of Hoxc9

Zhou, Bo; Wu, Xing; Wang, Jing; Yin, Yinliang; Zhu, Guang

doi:10.1016/j.bbapap.2008.01.021

Cited by 13 publications

(9 citation statements)

References 29 publications

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“…In particular, vertebrate and Drosophila SMADs, effectors of the TGF-beta and Decapentaplegic (Dpp) pathways, have been identified as Hox collaborators in several cis -regulatory elements (Galant et al , 2002; Grienenberger et al , 2003; Shi et al , 1999, 2001; Walsh and Carroll, 2007) (Table 3.1). Although SMAD-Hox-DNA-binding cooperativity has not been described, there are several reports suggesting that SMADs and Hox proteins can directly interact with each other (Wang et al , 2006; Williams et al , 2005; Zhou et al , 2008). Such interactions may be critical for building an enhanceosome-like structure on Hox-targeted cis -regulatory elements.…”

Section: Activity Regulation Of Hox Proteins: the Role Of Hox Collmentioning

confidence: 99%

Chapter 3 Hox Specificity

Mann

Lelli

Joshi

2009

Current Topics in Developmental Biology

311

245

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Hox proteins are well known for executing highly specific functions in vivo, but our understanding of the molecular mechanisms underlying gene regulation by these fascinating proteins has lagged behind. The premise of this review is that an understanding of gene regulation — by any transcription factor—requires the dissection of the cis-regulatory elements that they act upon. With this goal in mind, we review the concepts and ideas regarding gene regulation by Hox proteins and apply them to a curated list of directly regulated Hox cis-regulatory elements that have been validated in the literature. Our analysis of the Hox-binding sites within these elements suggests several emerging generalizations. We distinguish between Hox cofactors, proteins that bind DNA cooperatively with Hox proteins and thereby help with DNA-binding site selection, and Hox collaborators, proteins that bind in parallel to Hox-targeted cis-regulatory elements and dictate the sign and strength of gene regulation. Finally, we summarize insights that come from examining five X-ray crystal structures of Hox-cofactor-DNA complexes. Together, these analyses reveal an enormous amount of flexibility into how Hox proteins function to regulate gene expression, perhaps providing an explanation for why these factors have been central players in the evolution of morphological diversity in the animal kingdom.

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Section: Activity Regulation Of Hox Proteins: the Role Of Hox Collmentioning

confidence: 99%

Chapter 3 Hox Specificity

Mann

Lelli

Joshi

2009

Current Topics in Developmental Biology

311

245

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show abstract

“…The defects may have been caused by the reduced production associated with these genes. Zhou et al (2008) used three techniques, GST pull-down assays, surface plasmon resonance analysis, and multidimensional nuclear magnetic resonance, to analyze the interaction between the recombinant homeodomain (HD) of Hoxc9 and the MH1 domain of Smad4. He found that Smad4-MH1 can interact with the N-terminal part of the HD of Hoxc9, which, in turn, inhibits its transcriptional activity.…”

Section: Discussionmentioning

confidence: 99%

“…The Hoxc9 gene is required for the development of the neural tube in the mouse embryo, and disruptions in this gene lead to a deformed heart (Shashikant and Ruddle, 1996). Over the last few decades, SMAD4 has been identified as a CHD-causing gene (Qi et al, 2007), and Smad4-MH1 could occupy one of the DNA binding sites on Hoxc9, inhibiting its transcription activity (Zhou et al, 2008). From the results of these investigations, we predicted that Hoxc9 may play a role in the development of CHD.…”

Section: Introductionmentioning

confidence: 99%

Homeobox C9 Is Not Potentially Related to Congenital Heart Disease in Chinese Patients

Sun

Cheng

Li³

et al. 2012

Genetic Testing and Molecular Biomarkers

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“…Different studies described interactions between several other Hox and Smad proteins, [48][49][50] suggesting that the mechanisms behind this are probably complex. Importantly, the specific portion of Smad4 (MH1-c) encodes a peptide of 20 amino acids (127-147 of Smad4) which correspond to the region within the MH1 amino-terminus of Smad4 (101-148 of Smad4) that has been described in vitro to interact with Hoxa9.…”

Section: Discussionmentioning

confidence: 99%

Smad4 binds Hoxa9 in the cytoplasm and protects primitive hematopoietic cells against nuclear activation by Hoxa9 and leukemia transformation

Quéré

Karlsson

Hertwig³

et al. 2011

Blood

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We studied leukemic stem cells (LSCs) in a Smad4(-/-) mouse model of acute myelogenous leukemia (AML) induced either by the HOXA9 gene or by the fusion oncogene NUP98-HOXA9. Although Hoxa9-Smad4 complexes accumulate in the cytoplasm of normal hematopoietic stem cells and progenitor cells (HSPCs) transduced with these oncogenes, there is no cytoplasmic stabilization of HOXA9 in Smad4(-/-) HSPCs, and as a consequence increased levels of Hoxa9 is observed in the nucleus leading to increased immortalization in vitro. Loss of Smad4 accelerates the development of leukemia in vivo because of an increase in transformation of HSPCs. Therefore, the cytoplasmic binding of Hoxa9 by Smad4 is a mechanism to protect Hoxa9-induced transformation of normal HSPCs. Because Smad4 is a potent tumor suppressor involved in growth control, we developed a strategy to modify the subcellular distribution of Smad4. We successfully disrupted the interaction between Hoxa9 and Smad4 to activate the TGF-β pathway and apoptosis, leading to a loss of LSCs. Together, these findings reveal a major role for Smad4 in the negative regulation of leukemia initiation and maintenance induced by HOXA9/NUP98-HOXA9 and provide strong evidence that antagonizing Smad4 stabilization by these oncoproteins might be a promising novel therapeutic approach in leukemia.

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MH1 domain of SMAD4 binds N-terminal residues of the homeodomain of Hoxc9

Cited by 13 publications

References 29 publications

Chapter 3 Hox Specificity

Chapter 3 Hox Specificity

Homeobox C9 Is Not Potentially Related to Congenital Heart Disease in Chinese Patients

Smad4 binds Hoxa9 in the cytoplasm and protects primitive hematopoietic cells against nuclear activation by Hoxa9 and leukemia transformation

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