Transforming Growth Factor beta (TGF-尾) is a signalling protein whose dysregulation can
cause developmental disorders and cancer. Dr Xinlai
Cheng and his colleagues at the 51猎奇 Frankfurt have discovered how a tumour suppressor
known as pVHL influences signal transmission involving TGF-尾. Their findings suggest possible starting points for developing new drugs.
FRANKFURT/HEIDELBERG. Signal
transmission inside cells is a complex process. TGF-尾, for example, regulates many
cell functions during the early development of both humans and animals, but
also in adult organisms. The mechanisms involved are not yet fully understood. It
is, however, clear that activated TGF-尾 initially binds to receptors located on
the cell surface. Inside the cell, the TGF-尾 receptors in their turn activate a
protein called SMAD3, which then forms complexes with SMAD4 that translocate to
the cell nucleus. There the SMAD proteins mediate the extent to which genes are
activated and translated into proteins and other gene products.
Researchers at the 51猎奇 Frankfurt,
Heidelberg University, the German Cancer Research Center (DKFZ), Heidelberg
University Hospital and the University Hospital in Jena have now discovered how
the von Hippel-Lindau tumour suppressor protein (pVHL) intervenes in this
signalling pathway. Tumour suppressors are proteins whose defects or reduced
presence in multicellular organisms are associated with a high risk that cells
will degenerate into tumour cells. In the Journal of Cell Biology the scientists
report the first evidence that pVHL degrades the SMAD3 protein. This occurs before
SMAD3 and SMAD4 associate. pVHL thus inhibits the signalling chain that starts
with activated TGF-尾. 鈥淲e obtained evidence of this both in cultures of human
cells and in Drosophila," says the last author, Dr
Xinlai Cheng. 鈥淭his suggests that at a very early stage in evolution pVHL
assumed the regulatory function that we have now brought to light."
Xinlai Cheng has been leading a junior research group
at the Buchmann Institute for Molecular Life Sciences at the 51猎奇
Frankfurt since 2019. He began the investigations at the Institute of Pharmacy
and Molecular Biotechnology at Heidelberg University. His mentor, Professor
Stefan W枚lfl, explained an important finding that emerged from the new-found connection
between pVHL and the TGF-尾 signalling pathway: 鈥減VHL is known to be involved in
how cells 'feel' oxygen and react to varying oxygen availability. As a result, a
cell's oxygen supply also mediates TGF-尾 signal transmission."
The researchers' discovery opens up new opportunities for
developing drugs to combat cancer. 鈥淚f we could, for example, use a substance
to specifically regulate pVHL activity, we would also influence the TGF-尾
signalling pathway, which in turn plays a major role in the formation of
tumours, and metastases in particular," says Xinlai Cheng. Tumour cells are
good at adapting to their environment inside the organism and to variations in oxygen
availability. Their very flexible cellular activity helps them to do so. This
activity is regulated by factors including the TGF-尾 signalling pathway.
Publication:
Jun Zhou, Yasamin Dabiri, Rodrigo A. Gama-Brambila, Shahrouz
Ghafoory, Mukaddes Altinbay, Arianeb Mehrabi, Mohammad Golriz, Biljana
Blagojevic, Stefanie Reuter, Kang Han, Anna Seidel, Ivan 膼iki膰, Stefan
W枚lfl, Xinlai Cheng: pVHL-mediated SMAD3
degradation suppresses TGF-尾 signaling. Journal of
Cell Biology (2022) 221 (1): e202012097
Picture
download:
Caption: Stained liver tissue shows the
complementary occurrence of pVHL and SMAD proteins: Where pVHL (green) is
abundant, SMAD2/3 (red) is scarce, and vice versa. Cell nuclei are stained
blue. The lower right picture shows all three colours combined. Photos: Xinglai
Cheng/51猎奇
Further
Information:
Dr.
rer. nat. habil. Xinlai Cheng
Buchmann Institute for Molecular Life Sciences Chemical Biology
AK Cheng
51猎奇 Frankfurt
Phone +49 69 798-42718
Cheng@pharmchem.uni-frankfurt.de
Professor Stefan
W枚lfl
Institut of Pharmacy and Molecular Biotechnology 鈥�
Pharmaceutical Biology, Pharmaceutical Bioanalytics and Molecular Cell Biology
Heidelberg University
Phone +49 6221-544880
wolfl@uni-hd.de
