Cell News 01/2017
37
Endothelial Basement Membrane Laminin 511
Contributes to Endothelial Tightness
Jian Song, Xueli Zhang, Konrad Buscher, Ying Wang, Huiyu Wang, Jacopo Di Russo, Lixia Li,
Stefan Lütke-Enking, Alexander Zarbock, Anika Stadtmann, Paul Striewski, Benedikt Wirth,
Ivan Kuzmanov, Heinz Wiendl, Dörte Schulte, Dietmar Vestweber, Lydia Sorokin
Presenting author: Jian Song
Institute of Physiological Chemistry and Pathobiochemistry,
University of Muenster, Muenster, Germany
During leukocyte extravasation in inflammation, leukocytes
transmigrate across the endothelial cell monolayer and subse-
quently the underlying endothelial cell basement membrane.
While considerable information is available on the leukocyte
transmigration across the endothelial layer, subsequent pene-
tration of the basement membrane remains poorly understood.
Using intravital live imaging we show that transmigration of
the endothelial basement membrane is a rate-limiting step,
taking up to 40 min compared to 4 min required for penetra-
tion of the endothelial monolayer. We have previously reported
that the distribution of endothelial laminin isoforms varies
along the length of basement membranes underlying post-
capillary venules, with laminin 411 being ubiquitously ex-
pressed and laminin 511 showing areas of high and low or no
expression. Using the mice lacking laminin
α
5 in endothelial
basement membranes, we demonstrate that in addition to the
direct effect on leukocyte transmigration, laminin 511 affects
endothelial barrier function by stabilizing VE-cadherin at
junctions and down-regulating expression of CD99L2, correlat-
ing with reduced neutrophil extravasation. Data suggest that
endothelial adhesion to laminin 511 via
β
1 and
β
3 integrins
mediates RhoA-induced VE-cadherin localization to cell-cell
borders and, while CD99L2 downregulation requires integ-
rin
β
1, it is RhoA-independent, suggesting that laminin 511
can induce different intracellular signals that affect differ-
ent aspects of endothelial physiology. Our data demonstrate
that molecular information provided by basement membrane
laminin 511 plays a role both directly by affecting immune cell
migration patterns and indirectly by affecting the endothelial
barrier per se.
Song J, et al. (2017) Endothelial basement membrane laminin
511 contributes to endothelial junctional tightness and thereby
inhibits leukocyte transmigration. Cell Rep. Jan 31;18(5):
1256–1269.
OTHER TOPICS
Transcriptional expression of the proliferation marker Ki-67
Sigrid Uxa*, Paola Castillo-Binder*, Konstanze Stangner, Gerd A. Müller and Kurt Engeland
Presenting author: Sigrid Uxa
Molecular Oncology, Medical School, University of Leipzig,
Semmelweisstr. 14, 04103 Leipzig, Germany
Ki-67, the protein encoded by the human gene MKI67, is the
most frequently used proliferation marker in pathology for
cancer diagnostics. Although Ki-67 has been widely employed
as a diagnostic tool for more than two decades, the cellular
function and the regulation of the gene expression remained
largely unknown. Only recently, it was discovered that Ki-67
serves as a chromosome separator during mitosis and an orga-
nizer of heterochromatin. Ki-67 protein levels vary throughout
the cell cycle with an expression maximum in G2 phase. In
G0 Ki-67 is not expressed. Our experiments demonstrate that
MKI67 mRNA levels also fluctuate in a cell cycle-dependent
manner preceding expression of the protein. This observation
suggests that Ki-67 expression is controlled on the transcrip-
tional level. Indeed, we show that MKI67 expression is mainly
regulated via two CHR transcriptional elements together with
a CDE promoter site. Remarkably, all three sites are involved
in transcriptional repression as well as activation of MKI67
through binding of the DREAM and MMB transcription factor
complexes, respectively. This promoter structure represents a
novel type of MuvB target genes. Therefore, we identify the
mechanism of MKI67 cell cycle-dependent transcriptional
regulation and explain the long observed expression pattern of
the Ki-67 proliferation marker.
