TY  - JOUR
A1  - Seher, Axel
A1  - Lagler, Charlotte
A1  - Stühmer, Thorsten
A1  - Müller-Richter, Urs Dietmar Achim
A1  - Kübler, Alexander Christian
A1  - Sebald, Walter
A1  - Müller, Thomas Dieter
A1  - Nickel, Joachim
T1  - Utilizing BMP-2 muteins for treatment of multiple myeloma
JF  - PLoS ONE
N2  - Multiple myeloma (MM) represents a haematological cancer characterized by the pathological hyper proliferation of antibody-producing B-lymphocytes. Patients typically suffer from kidney malfunction and skeletal disorders. In the context of MM, the transforming growth factor β (TGFβ) member Activin A was recently identified as a promoter of both accompanying symptoms. Because studies have shown that bone morphogenetic protein (BMP)-2-mediated activities are counteracted by Activin A, we analysed whether BMP2, which also binds to the Activin A receptors ActRII and ActRIIB but activates the alternative SMAD-1/5/8 pathway, can be used to antagonize Activin A activities, such as in the context of MM. Therefore three BMP2 derivatives were generated with modified binding activities for the type II (ActRIIB) and/or type I receptor (BMPRIA) showing either increased or decreased BMP2 activity. In the context of MM these BMP2 muteins show two functionalities since they act as a) an anti-proliferative/apoptotic agent against neoplastic B-cells, b) as a bone-formation promoting growth factor. The molecular basis of both activities was shown in two different cellular models to clearly rely on the properties of the investigated BMP2 muteins to compete for the binding of Activin A to the Activin type II receptors. The experimental outcome suggests new therapeutic strategies using BMP2 variants in the treatment of MM-related pathologies.
KW  - multiple myeloma
KW  - signaling
KW  - cell proliferation
KW  - cell binding
KW  - membrane receptor signaling
KW  - BMP
KW  - gene expression
KW  - B cell receptors
KW  - B cells
Y1  - 2017
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-158144
VL  - 12
IS  - 5
ER  - 
TY  - JOUR
A1  - Rudel, Thomas
A1  - Prusty, Bhupesh K.
A1  - Siegl, Christine
A1  - Gulve, Nitish
A1  - Mori, Yasuko
T1  - GP96 Interacts with HHV-6 during Viral Entry and Directs It for Cellular Degradation
N2  - CD46 and CD134 mediate attachment of Human Herpesvirus 6A (HHV-6A) and HHV-6B to host cell, respectively. But many cell types interfere with viral infection through rapid degradation of viral DNA. Hence, not all cells expressing these receptors are permissive to HHV-6 DNA replication and production of infective virions suggesting the involvement of additional factors that influence HHV-6 propagation. Here, we used a proteomics approach to identify other host cell proteins necessary for HHV-6 binding and entry. We found host cell chaperone protein GP96 to interact with HHV-6A and HHV-6B and to interfere with virus propagation within the host cell. In human peripheral blood mononuclear cells (PBMCs), GP96 is transported to the cell surface upon infection with HHV-6 and interacts with HHV-6A and -6B through its C-terminal end. Suppression of GP96 expression decreased initial viral binding but increased viral DNA replication. Transient expression of human GP96 allowed HHV-6 entry into CHO-K1 cells even in the absence of CD46. Thus, our results suggest an important role for GP96 during HHV-6 infection, which possibly supports the cellular degradation of the virus.
KW  - host cells
KW  - immunoprecipitation
KW  - HeLa cells
KW  - antibodies
KW  - cell binding
KW  - viral transmission and infection
KW  - viral entry
KW  - flow cytometry
Y1  - 2014
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-111068
ER  -