Homeodomain proteins in development and therapy

Dorn, Arnulf; Affolter, Markus; Gehring, Walter J.; Leupin, Werner

doi:10.1016/0163-7258(94)90061-2

Cited by 19 publications

(17 citation statements)

References 167 publications

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“…For example, the interactions of charged amino acid side-chains with the DNA are clearly subject to electrostatic in¯uences. Properly understanding the effects of mutating such residues on the HD-DNA binding af®nity may be of great help in the rational design of HDs, both for reasearch (Pomerantz et al, 1995a,b;Shang et al, 1995) and possibly practical applications (Dorn et al, 1994). Electrostatics may also make a contribution to the temperature dependence of the protein-DNA binding constant, an effect more generally attributed to hydrophobic effects (Ha et al, 1989;Spolar & Record, 1994).…”

Section: Introductionmentioning

confidence: 98%

Electrostatic effects in homeodomain-DNA interactions

Fogolari

Elcock

Esposito

et al. 1997

Journal of Molecular Biology

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Section: Introductionmentioning

confidence: 98%

Electrostatic effects in homeodomain-DNA interactions

Fogolari

Elcock

Esposito

et al. 1997

Journal of Molecular Biology

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“…Homeobox genes, coding for homeodomaincontaining factors, were first described in Drosophila, where expression is linked to the establishment of tissue identity [Dorn et al, 1994;Gehrig et al, 1994]. It has also been postulated that some of the homeodomaincontaining factors activate tissue-specific genes [Bodner et al, 1988;Ingraham et al, 1988;Zhao et al, 1994;Lints et al, 1993;Komuro and Izumo, 1993].…”

mentioning

confidence: 97%

HOXB7 overexpression promotes differentiation of C3H10T1/2 cells to smooth muscle cells

et al. 2000

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The presence of immature smooth muscle cells and ectopic tissues such as fully-formed bone in atherosclerotic lesions, may result from recapitulation of embryonic mechanisms in the artery wall. We hypothesized that expression of homeobox genes is triggered in atherogenesis and that these regulate proliferation and differentiation of multipotential progenitor cells along one or more specific lineages. We identified expression of the homeobox gene HOXB7 in clones of bovine aortic medial cells previously shown to be multipotent. HOXB7 was subsequently detected in human atherosclerotic plaques by RT-PCR and in situ hybridization. Expression was localized to areas adjacent to calcification and scattered in media and neointima, which may be reflective of a role in either osteoblastic or smooth muscle cell differentiation. To differentiate between these possibilities, we overexpressed HOXB7 in C3H10T1/2 cells, a multipotent cell line able to differentiate into vascular smooth muscle cells (SMC), as well as osteogenic and chondrogenic lineages. Results showed that overexpression of HOXB7 increased proliferation 3.5-fold, and induced an SMC-like cell morphology. In addition, expression of the early SMC markers calponin and SM22alpha increased 4-fold and 3-fold respectively by semi-quantitative RT-PCR. Expression of the intermediate SMC marker smooth muscle myosin heavy chain (SM-MHC) did not change. No increase in osteogenic or chondrogenic differentiation was detected, neither in the C3H10T1/2 cells nor in M2 cells, a bone marrow stromal cell line used to confirm this result. These findings suggest that HOXB7 plays a role in expansion of immature cell populations or dedifferentiation of mature cells.

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“…This peptide was linked to the antennapedia sequence RQIKIWFQNRRMKWKK that has been shown to enter cells efficiently and induce minimal toxicity (54,55). As a control, a mutant peptide YPYAAGEARGAP was fused to the same antennapedia sequence.…”

Section: Resultsmentioning

confidence: 99%

A Herpes Simplex Virus Scaffold Peptide That Binds the Portal Vertex Inhibits Early Steps in Viral Replication

Yang

Wills

Baines

2013

J Virol

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Previous experiments identified a 12-amino-acid (aa) peptide that was sufficient to interact with the herpes simplex virus 1 (HSV-1) portal protein and was necessary to incorporate the portal into capsids. In the present study, cells were treated at various times postinfection with peptides consisting of a portion of the Drosophila antennapedia protein, previously shown to enter cells efficiently, fused to either wild-type HSV-1 scaffold peptide (YPYYPGEARGAP) or a control peptide that contained changes at positions 4 and 5. These 4-tyrosine and 5-proline residues are highly conserved in herpesvirus scaffold proteins and were previously shown to be critical for the portal interaction. Treatment early in infection with subtoxic levels of wild-type peptide reduced viral infectivity by over 1,000-fold, while the mutant peptide had little effect on viral yields. In cells infected for 3 h in the presence of wild-type peptide, capsids were observed to transit to the nuclear rim normally, as viewed by fluorescence microscopy. However, observation by electron microscopy in thin sections revealed an aberrant and significant increase of DNA-containing capsids compared to infected cells treated with the mutant peptide. Early treatment with peptide also prevented formation of viral DNA replication compartments. These data suggest that the antiviral peptide stabilizes capsids early in infection, causing retention of DNA within them, and that this activity correlates with peptide binding to the portal protein. The data are consistent with the hypothesis that the portal vertex is the conduit through which DNA is ejected to initiate infection. Herpesviruses cause a number of important diseases in animals and humans, including recurrent skin lesions, blindness, birth defects, transplant rejection, encephalitis, and lymphoid neoplasia. The viral thymidine kinase is by far the most common target of existing antiherpesvirus therapies. This kinase phosphorylates acyclovir and many of its derivatives, making them bioavailable to the replicating viral DNA polymerase (1). Depending on the compound, incorporation of the triphosphorylated drug into the elongating DNA either acts as a competitor for nucleotides, resulting in stalling of the DNA polymerase, or, like acyclovir, precludes formation of further phosphodiester bonds and terminates DNA replication because the drug lacks a 3= hydroxyl group (2). Because acyclovir and its derivatives represent the most common treatment for herpesvirus infections, and thymidine kinase is ultimately dispensable for viral replication, viral resistance to this group of compounds is common and represents an important threat to human health (3, 4).Several novel compounds have recently yielded promising results and may eventually expand the antiherpesvirus pharmacopeia (reviewed in reference 5). Different compounds target the viral helicase/primase (6), a conserved viral protein kinase (7-11), and the viral terminase, which is a 3-component enzyme that endonucleolytically cleaves viral DNA from concateme...

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Homeodomain proteins in development and therapy

Cited by 19 publications

References 167 publications

Electrostatic effects in homeodomain-DNA interactions

Electrostatic effects in homeodomain-DNA interactions

HOXB7 overexpression promotes differentiation of C3H10T1/2 cells to smooth muscle cells

A Herpes Simplex Virus Scaffold Peptide That Binds the Portal Vertex Inhibits Early Steps in Viral Replication

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