Patched1 functions as a gatekeeper by promoting cell cycle progression.

Adolphe C, Hetherington R, Ellis T, Wainwright B.

Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia.

Mutations in the Hedgehog receptor, Patched 1 (Ptch1), have been linked to both familial and sporadic forms of basal cell carcinoma (BCC), leading to the hypothesis that loss of Ptch1 function is sufficient for tumor progression. By combining conditional knockout technology with the inducible activity of the Keratin6 promoter, we provide in vivo evidence that loss of Ptch1 function from the basal cell population of mouse skin is sufficient to induce rapid skin tumor formation, reminiscent of human BCC. Elimination of Ptch1 does not promote the nuclear translocation of beta-catenin and does not induce ectopic activation or expression of Notch pathway constituents. In the absence of Ptch1, however, a large proportion of basal cells exhibit nuclear accumulation of the cell cycle regulators cyclin D1 and B1. Collectively, our data suggest that Ptch1 likely functions as a tumor suppressor by inhibiting G1-S phase and G2-M phase cell cycle progression, and the rapid onset of tumor progression clearly indicates Ptch1 functions as a "gatekeeper." In addition, we note the high frequency and rapid onset of tumors in this mouse model makes it an ideal system for testing therapeutic strategies, such as Patched pathway inhibitors.
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Gene Ther. 2006 Mar 2;
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Gene therapy, angiogenesis, Sonic Hedgehog: Sonic The Hedgehog to the rescue?

Donahue JK.

1MetroHealth Hospital, Case Western Reserve University School of Medicine, Heart and Vascular Research Center, Rammelkamp 653, 2500 MetroHealth Drive, Cleveland, OH 44109, USA.

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Nat Immunol. 2006 Mar 5; [Epub ahead of print] Related Articles, Links
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Hedgehog signaling controls thymocyte progenitor homeostasis and differentiation in the thymus.

Andaloussi AE, Graves S, Meng F, Mandal M, Mashayekhi M, Aifantis I.

[1] Department of Medicine, Section of Rheumatology, University of Chicago, Chicago, Illinois 60637, USA. [2] Immuno-Hematology Section, Pasteur Institute of Morocco, Casablanca 20100, Morocco. [3] These authors contributed equally to this work.

Commitment of hematopoietic progenitors to the T cell lineage requires the integration of multiple signaling pathways. Evidence has suggested involvement of hedgehog (Hh) signaling in T cell differentiation through its signal transducer smoothened (Smo). However, the precise function of the Hh pathway remains controversial, mainly because T cell-specific in vivo genetic models have not been used. Using pre-T cell-specific, mature T cell-specific and poly(I).poly(C)-inducible deletions of Smo and antagonists of Smo signaling, we report here that Hh is an essential positive regulator of T cell progenitor differentiation. Furthermore, we localize Hh function to a stage preceding pre-T cell receptor signaling, connect Smo signaling to the activity of the Gli1 and Gli2 transcription factors and demonstrate that Hh affects regulators of thymocyte survival and proliferation.

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Med Hypotheses. 2006 Mar 4; [Epub ahead of print] Related Articles, Links
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Angiogenic gene therapy as a potential therapeutic agent in chronic osteomyelitis.

Ross JJ.

Division of Infectious Diseases, Caritas Saint Elizabeth's Medical Center, 736 Cambridge Street, Boston, MA 02135, USA.

Bacterial osteomyelitis is common, and outcomes are often poor. Standard therapies fail in 31% of cases, and lower extremity amputation and loss of independent functional status are common. Innovative therapies are desperately needed, particularly in diabetic patients with peripheral vascular disease at high risk for bad outcomes. Angiogenic gene therapy is a novel, logical and promising approach in these patients. Adult bone is not well vascularized. Host inflammation and bacterial toxin production result in further loss of vascularity, and produce bone necrosis. Dead bone acts as a foreign body, and is permissive for persistent infection. Poor blood supply prevents remodeling of dead bone, delivery of antibiotics, and phagocytosis of bacteria. Therefore, angiogenic gene therapy may be a useful therapeutic agent in osteomyelitis. It is reasonable to pursue studies of angiogenic agents in established animal models of chronic osteomyelitis, not only with vascular endothelial growth factor (VEGF), but also with the powerful bone angiogenic agent, placental growth factor, as well as other agents with tissue regenerative and angiogenic potential, such as sonic hedgehog, bone morphogenetic proteins, matrix metalloproteinase-9, secretoneurin, and perhaps pluripotent stem cells. If successful, animal studies could lead to pilot studies of one or more of these agents as adjunctive therapy, in addition to antibiotics, in diabetic patients with chronic osteomyelitis who have failed conventional treatment.

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BMC Cancer. 2006 Mar 7;6(1):54 [Epub ahead of print] Links
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Cross-platform expression profiling demonstrates that SV40 small tumor antigen activates Notch, Hedgehog, and Wnt signaling in human cells.

Ali-Seyed M, Laycock N, Karanam S, Xiao W, Blair ET, Moreno CS.

ABSTRACT: BACKGROUND: We previously analyzed human embryonic kidney (HEK) cell lines for the effects that simian virus 40 (SV40) small tumor antigen (ST) has on gene expression using Affymetrix U133 GeneChips. To cross-validate and extend our initial findings, we sought to compare the expression profiles of these cell lines using an alternative microarray platform. METHODS: We have analyzed matched cell lines with and without expression of SV40 ST using an Applied Biosystems (AB) microarray platform that uses single 60-mer oligonucleotides and single-color quantitative chemiluminescence for detection. RESULTS: While we were able to previously identify only 456 genes affected by ST with the Affymetrix platform, we identified 1927 individual genes with the AB platform. Additional technical replicates increased the number of identified genes to 3478 genes and confirmed the changes in 278 (61%) of our original set of 456 genes. Among the 3200 genes newly identified as affected by SV40 ST, we confirmed 20 by QRTPCR including several components of the Wnt, Notch, and Hedgehog signaling pathways, consistent with SV40 ST activation of these developmental pathways. While inhibitors of Notch activation had no effect on cell survival, cyclopamine had a potent killing effect on cells expressing SV40 ST. CONCLUSIONS: These data show that SV40 ST expression alters cell survival pathways to sensitize cells to the killing effect of Hedgehog pathway inhibitors.

Be interesting to see what happens with this new information...