Dev Cell. 2006 Feb;10(2):177-86. Related Articles, Links

Divergence of Hedgehog Signal Transduction Mechanism between Drosophila and Mammals.

Varjosalo M, Li SP, Taipale J.

Molecular and Cancer Biology Program, Biomedicum, University of Helsinki and Department of Molecular Medicine, National Public Health Institute, P.O. Box 63, Helsinki FIN-00014, Finland.

The Hedgehog (Hh) signaling pathway has conserved roles in development of species ranging from Drosophila to humans. Responses to Hh are mediated by the transcription factor Cubitus interruptus (Ci; GLIs 1-3 in mammals), and constitutive activation of Hh target gene expression has been linked to several types of human cancer. In Drosophila, the kinesin-like protein Costal2 (Cos2), which associates directly with the Hh receptor component Smoothened (Smo), is essential for suppression of the transcriptional activity of Ci in the absence of ligand. Another protein, Suppressor of Fused (Su(Fu)), exerts a weak negative influence on Ci activity. Based on analysis of functional and sequence conservation of Cos2 orthologs, Su(Fu), Smo, and Ci/GLI proteins, we find here that Drosophila and mammalian Hh signaling mechanisms have diverged, and that, in mouse cells, major Cos2-like activities are absent and the inhibition of the Hh pathway in the absence of ligand critically depends on Su(Fu).

Dev Cell. 2006 Feb;10(2):187-97.
Genetic elimination of suppressor of fused reveals an essential repressor function in the Mammalian hedgehog signaling pathway.

Svard J, Henricson KH, Persson-Lek M, Rozell B, Lauth M, Bergstrom A, Ericson J, Toftgard R, Teglund S.

Department of Biosciences at Novum, Karolinska Institutet, SE-141 57 Huddinge, Sweden.

The Hedgehog (Hh) pathway plays important roles during embryogenesis and carcinogenesis. Here, we show that ablation of the mouse Suppressor of fused (Sufu), an intracellular pathway component, leads to embryonic lethality at approximately E9.5 with cephalic and neural tube defects. Fibroblasts derived from Sufu(-/-) embryos showed high Gli-mediated Hh pathway activity that could not be modulated at the level of Smoothened and could only partially be blocked by PKA activation. Despite the robust constitutive pathway activation in the Sufu(-/-) fibroblasts, the GLI1 steady-state localization remained largely cytoplasmic, implying the presence of an effective nuclear export mechanism. Sufu(+/-) mice develop a skin phenotype with basaloid changes and jaw keratocysts, characteristic features of Gorlin syndrome, a human genetic disease linked to enhanced Hh signaling. Our data demonstrate that, in striking contrast to Drosophila, in mammals, Sufu has a central role, and its loss of function leads to potent ligand-independent activation of the Hh pathway.

Curis current inhibitors block the Hh signal at the SMO level of the pathway. This article abstract could mean that if there is a mutation in Sufu then the current Hh inhibitor would NOT be effective.

I don't have the article and can only speculate about "High Gli-mediated Hh pathway activity that could not be modulated at the level of Smoothened and could only partially be blocked by PKA activation."

Post again when I have to article.

After reading the article... As I suspected from the abstract, the smo antagonist will not work if cancers are null for SUFU.

“To address the question of whether the observed Glimediated
Hh signaling activity in the Sufu2/2 MEF cells
can be further stimulated, we incubated the Sufu2/2
MEF cells with or without a concentration of Smo agonist
(SAG) that has been shown to fully activate the Hh
pathway (Chen et al., 2002). No further increase in Gli reporter
activity could be observed (Figure 4C), suggesting
that in the absence of Sufu, activation of Smo could
not induce additional Gli-mediated transcriptional activity.
Conversely, we tested whether cyclopamine, a
known inhibitor of the Hh pathway that acts on Smo,
could inhibit Gli reporter activity (Taipale et al., 2000).
However, again, no effect was observed (Figure 4C), indicating
that neither stimulation nor inhibition of the Hh
pathway at the level of Smo has any significant effect
on Gli activity in the absence of Sufu.”

However, based on expression studies of cancers samples, I believe that this is a rare event. Once again the Hh pathway mechanism takes a bizarre twist. Be interesting if any other studies come out to support this idea.

"Concluding Remarks
The results presented in this study highlight an important
evolutionary divergence in the basic regulatory circuits
controlling Hh signaling, a pathway having a key
role in development and human disease, including cancer,
thereby illustrating the need to understand in detail
the function of the pathway in mammalian systems. The
unanticipated role of Sufu as a specific and potent repressor
of Hh signaling also opens new therapeutic avenues
to control deregulated Hh pathway activation, for
example, by development of Sufu mimetics."

Curr Opin Gastroenterol. 2006 Mar;22(2):90-94. Related Articles, Links

Molecular biology of the small intestine.

Ahuja V, Dieckgraefe BK, Anant S.

aDepartment of Gastroenterology, All India Institute of Medical Sciences, New Delhi, India bDepartment of Internal Medicine, Washington University School of Medicine, St Louis, Missouri, USA cDepartment of Molecular Biology and Pharmacology, Washington University School of Medicine, St Louis, Missouri, USA.

PURPOSE OF REVIEW: A concise report of published research is presented here that has provided new insights into the molecular and cell biology of the small intestine. RECENT FINDINGS: The precise control of cell renewal lineage commitment, differentiation and apoptosis along the crypt-villus axis are regulated by paracrine and autocrine signaling pathways that include Wnt, Hedgehog and Notch ligands. The downstream signaling pathways and transcriptional control of gene expression are being elucidated. Conditional loss of functional c-myc in the intestinal mucosa may have no effect on the normal homeostasis of this tissue. Manipulation of CUGBP2 expression may modulate the response of normal intestine to radiation therapy. SUMMARY: The cellular interactions at various levels in the small intestine are being understood and would provide a framework for interventional translational research in coming years.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16462162&query_hl=2&itool=pubmed_docsum

Development. 2006 Feb 15;

(2006)Early Hedgehog signaling from neural to oral epithelium organizes anterior craniofacial development.

Eberhart JK, Swartz ME, Crump JG, Kimmel CB.

Hedgehog (Hh) signaling plays multiple roles in the development of the anterior craniofacial skeleton. We show that the earliest function of Hh is indirect, regulating development of the stomodeum, or oral ectoderm. A subset of post-migratory neural crest cells, that gives rise to the cartilages of the anterior neurocranium and the pterygoid process of the palatoquadrate in the upper jaw, condenses upon the upper or roof layer of the stomodeal ectoderm in the first pharyngeal arch. We observe that in mutants for the Hh co-receptor smoothened (smo) the condensation of this specific subset of crest cells fails, and expression of several genes is lost in the stomodeal ectoderm. Genetic mosaic analyses with smo mutants show that for the crest cells to condense the crucial target tissue receiving the Hh signal is the stomodeum, not the crest. Blocking signaling with cyclopamine reveals that the crucial stage, for both crest condensation and stomodeal marker expression, is at the end of gastrulation - some eight to ten hours before crest cells migrate to associate with the stomodeum. Two Hh genes, shh and twhh, are expressed in midline tissue at this stage, and we show using mosaics that for condensation and skeletogenesis only the ventral brain primordium, and not the prechordal plate, is an important Hh source. Thus, we propose that Hh signaling from the brain primordium is required for proper specification of the stomodeum and the stomodeum, in turn, promotes condensation of a subset of neural crest cells that will form the anterior neurocranial and upper jaw cartilage.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16481351&query_hl=1&itool=pubmed_docsum

Genes Dev. 2006 Feb 15;20(4):399-410.

CKI, there's more than one: casein kinase I family members in Wnt and Hedgehog signaling.

Price MA.

Centre for Developmental and Biomedical Genetics, Department of Biomedical Science, University of Sheffield, Sheffield S10 2TN, United Kingdom.

Multiple members of the casein kinase I family of serine/threonine protein kinases are involved in positive and negative roles in Wnt and Hedgehog signaling. Here I review these roles, including recent results on casein kinase I (CKI) phosphorylation and activation of LRP6, and CKI phosphorylation of Ci and mediation of Ci-Slimb/beta-TrCP binding.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16481469&query_hl=1&itool=pubmed_docsum