"These results demonstrate a functional similarity between HPV16 E7, SV40 large T and adenovirus E1a and suggest that these genes may immortalize cells by a common mechanism. Interestingly, the limited sequence homology between these three gene products is restricted to the domain which has recently been implicated in binding the retinoblastoma gene product."

and

"Conditional neuronal simian virus 40 T antigen expression induces Alzheimer-like tau and amyloid pathology in mice."

and

http://jvi.asm.org/cgi/content/full/82/15/7252#R15
"Dyrk1A and -1B are highly related dual-specificity kinases that have been implicated in regulating cell survival, proliferation, and differentiation (86). It is unclear why E1A targets Dyrk1A and -1B, but the interaction with E1A stimulates their kinase activity in vitro and their binding overlaps the CtBP binding site (148). In an interesting parallel, the immortalization of keratinocytes by HPV16 E7 results in an increase in Dryk1A expression, and a similar increase in Dyrk1A expression is present in malignant HPV-positive cervical cancers, where it has been proposed to function as an antiapototic factor (15). E1A may utilize Dyrk1A as a survival factor in a manner similar to that of HPV E7, but this remains to be determined."

It's interesting that DYRK1A co-localizes with dynamin 1. Inhibition of dynamin 1 with dynasore blocks HPV16 entry. Several studies report that Abeta depletes dynamin 1. It would seem that depletion of Abeta would not be beneficial in an HPV16E7 infection as you may increase the viral load.

Mary


Oncogene. 1989 Feb;4(2):153-8.
Functional similarity between HPV16E7, SV40 large T and adenovirus E1a proteins.
Vousden KH, Jat PS.
Ludwig Institute for Cancer Research, St Mary's Hospital Medical School, London, UK.

We have analysed the immortalizing function of Human Papillomavirus type 16 (HPV16) in a rat cell line which has been derived by immortalizing rat embryo fibroblasts with a thermolabile SV40 large T antigen and is temperature sensitive for growth. Introduction of wild type SV40 large T antigen or the adenovirus E1a 12s gene product has previously been shown to readily overcome the inability of these cells to divide at the non-permissive temperature. In contrast, the introduction of myc, another known immortalizing gene, cannot complement the growth defect of these cells. This cell line therefore provides a novel assay system which can distinguish two groups of immortalizing oncogenes. We have shown here that expression of HPV16 can readily complement the growth defect in this rat cell line and that this function can be genetically localised to E7. Cells expressing HPV16 E6 sequences are also weakly rescued from growth arrest at the non-permissive temperature. These results demonstrate a functional similarity between HPV16 E7, SV40 large T and adenovirus E1a and suggest that these genes may immortalize cells by a common mechanism. Interestingly, the limited sequence homology between these three gene products is restricted to the domain which has recently been implicated in binding the retinoblastoma gene product.

PMID: 2538790 [PubMed - indexed for MEDLINE

J Neurosci. 2007 Mar 14;27(11):2969-78.


Conditional neuronal simian virus 40 T antigen expression induces Alzheimer-like tau and amyloid pathology in mice.
Park KH, Hallows JL, Chakrabarty P, Davies P, Vincent I.
Centre for Molecular Medicine and Therapeutics, Department of Pediatrics, Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia, Canada, V5Z 4H4.

A large body of evidence has shown the activation of a cohort of cell cycle regulators and the duplication of DNA in degenerating neurons of Alzheimer's disease (AD) brain. Activation of these regulators and duplication of chromosomes precede neurodegeneration and formation of neurofibrillary tangles (NFTs), one of the diagnostic lesions of AD. These findings, in combination with evidence for cell cycle regulation of amyloid precursor protein and tau, has led to the hypothesis that reentry into the cell cycle underlies AD pathogenesis. To test this hypothesis directly, we have created transgenic mice with forced cell cycle activation in postmitotic neurons via conditional expression of the simian virus 40 large T antigen (TAg) oncogene. We show that TAg mice recapitulate the cell cycle changes seen in AD and display a neurodegenerative phenotype accompanied by tau pathology and NFT-like profiles. Moreover, plaque-like amyloid deposits, similar to those seen in AD, are also observed in the brains of TAg mice. These data provide support for an essential role of ectopic cell cycle activation in the generation of the characteristic pathological hallmarks of AD. Furthermore, our TAg mice are the first model to develop NFTs and amyloid pathology simultaneously and in the absence of any human transgenes. These mice will be useful for further defining the nongenetic mechanisms in AD pathogenesis and for the development of cell cycle-based therapies for AD.

PMID: 17360920 [PubMed - indexed for MEDLINE]

Eur J Neurosci. 2003 Jun;17(11):2277-86. Links


Expression patterns and subcellular localization of the Down syndrome candidate protein MNB/DYRK1A suggest a role in late neuronal differentiation.
Hämmerle B, Carnicero A, Elizalde C, Ceron J, Martínez S, Tejedor FJ.
Instituto de Neurociencias, CSIC and Universidad Miguel Hernandez, San Juan, 03550 Alicante, Spain.

The Minibrain (Mnb) gene belongs to a new protein kinase family, which is evolutionarily conserved, and probably plays several roles during brain development and in adulthood. In Drosophila, mnb is involved in postembryonic neurogenesis and in learning/memory. In humans, MNB has been mapped within the Down syndrome critical region of chromosome 21 and is overexpressed in the Down syndrome embryonic brain. It has been widely proposed that MNB is involved in the neurobiological alterations associated with Down syndrome. Nevertheless, little is known about the functional role that MNB plays in vertebrate brain development. We have recently shown [Hämmerle et al. (2002) Dev. Biol., 246, 259-273] that in early vertebrate embryos, Mnb is transiently expressed in neural progenitor cells during the transition from proliferating to neurogenic divisions. Here we have studied in detail a second wave of Mnb expression, which takes place in the brain of intermediate and late vertebrate embryos. In these stages, MNB seems to be restricted to certain populations of neurons, as no consistent expression was detected in astroglial or oligodendroglial cells. Interestingly, MNB expression takes place at the time of dendritic tree differentiation and is initiated by a transient translocation from the cytoplasm to the nucleus. Afterwards, MNB protein is transported to the growing dendritic tree, where it colocalizes with Dynamin 1, a putative substrate of MNB kinases. We propose that MNB kinase is involved in the signalling mechanisms that regulate dendrite differentiation. This functional role helps to build a new hypothesis for the implication of MNB/DYRK1A in the developmental aetiology of Down syndrome neuropathologies.

PMID: 12814361 [PubMed - indexed for MEDLINE]

Am J Ther. 2008 Jul-Aug;15(4):304-11. Links

HPV16 and BPV1 infection can be blocked by the dynamin inhibitor dynasore.
Abban CY, Bradbury NA, Meneses PI.
School of Graduate and Postdoctoral Studies, H. M. Bligh Cancer Research Laboratory, Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL 60064, USA.

The initial entry of papillomaviruses into their target cells has been shown to occur by clathrin-mediated endocytosis and caveolae-mediated endocytosis. These mechanisms entail the formation of nascent-coated vesicles at the plasma membrane. Such coated vesicles, clathrin or caveolin, form and pinch-off in a controlled mechanism that involves several proteins including dynamin. Dynamin is a GTPase that forms a dynamin ring at the stem connecting the nascent vesicle to the plasma membrane. In a still not fully characterized mechanism, dynamin's contraction and twisting results in the scission of the vesicle. In an effort to better characterize the role and molecular mechanisms of dynamin's function, researchers have identified dynasore, a dynamin GTPase inhibitor that prevents the scission of dynamin-dependent endocytic vesicles. Here, we have tested if infection by pseudovirus corresponding to the oncogenic human papillomavirus type 16 and bovine papillomavirus type 1 can be blocked by dynasore. We present data demonstrating that dynasore can block infection of human papillomavirus type 16 and bovine papillomavirus type 1 pseudovirions in a dose- and time-dependent manner with equal efficiency. Presently, there is no available therapy that can block infection by a wide range of papillomavirus regardless of species or genotypes. Targeting dynamin may lead to the rational design of drug able to prevent infection by papillomaviruses, and by other infectious agents dependent on this protein for initial internalization into target cells. Whether such an approach will prove successful needs further investigation.

http://www.plosone.org/article/info:doi%2F10.1371%2Fjournal.pone.0009505

The Alzheimer's Disease-Associated Amyloid β-Protein Is an Antimicrobial Peptide

Thanks I.N.

Further to the posts above, I see that depletion of dynamin also inhibits C.albicans internalization. Moir and colleagues suggest that Abeta is an antimicrobial and that C.albicans infection is reported in the brain in Alzheimer's. They suggest that depletion of Abeta may have consequences in ALZ therapy due to this fact.

I'd suggested in Feb 09 that depletion of Abeta might not be a good idea as it inhibits dynamin and consequently the immune response. Their study supports my hypothesis.

Mary

Cell Microbiol. 2009 Aug;11(8):1179-89. Epub 2009 Mar 31.

Candida albicans internalization by host cells is mediated by a clathrin-dependent mechanism.
Moreno-Ruiz E, Galán-Díez M, Zhu W, Fernández-Ruiz E, d'Enfert C, Filler SG, Cossart P, Veiga E.

Institut Pasteur, Unité Biologie et Pathogénicité Fongiques, F-75015 Paris, France.

Candida albicans is a major cause of oropharyngeal, vulvovaginal and haematogenously disseminated candidiasis. Endocytosis of C. albicans hyphae by host cells is a prerequisite for tissue invasion. This internalization involves interactions between the fungal invasin Als3 and host E- or N-cadherin. Als3 shares some structural similarity with InlA, a major invasion protein of the bacterium Listeria monocytogenes. InlA mediates entry of L. monocytogenes into host cells through binding to E-cadherin. A role in internalization, for a non-classical stimulation of the clathrin-dependent endocytosis machinery, was recently highlighted. Based on the similarities between the C. albicans and L. monocytogenes invasion proteins, we studied the role of clathrin in the internalization of C. albicans. Using live-cell imaging and indirect immunofluorescence of epithelial cells infected with C. albicans, we observed that host E-cadherin, clathrin, dynamin and cortactin accumulated at sites of C. albicans internalization. Similarly, in endothelial cells, host N-cadherin, clathrin and cortactin accumulated at sites of fungal endocytosis. Furthermore, clathrin, dynamin or cortactin depletion strongly inhibited C. albicans internalization by epithelial cells. Finally, beads coated with Als3 were internalized in a clathrin-dependent manner. These data indicate that C. albicans, like L. monocytogenes, hijacks the clathrin-dependent endocytic machinery to invade host cells.

PMID: 19416270 [PubMed - indexed for MEDLINE]