In:
Journal of Cell Science, The Company of Biologists, Vol. 126, No. 2 ( 2013-01-15), p. 508-520
Kurzfassung:
The tumor suppressors Lats1 and Lats2 are mediators of the Hippo pathway that regulates tissue growth and proliferation. Their N-terminal non-kinase regions are distinct except for Lats conserved domains 1 and 2 (LCD1 and LCD2), which may be important for Lats1/2-specific functions. Lats1 knockout mice were generated by disrupting the N-terminal region containing LCD1 (Lats1ΔN/ΔN). Some Lats1ΔN/ΔN mice were born safely and grew normally. However, mouse embryonic fibroblasts (MEFs) from Lats1ΔN/ΔN mice displayed mitotic defects, centrosomal overduplication, chromosomal misalignment, multipolar spindle formation, chromosomal bridging and cytokinesis failure. They also showed anchorage-independent growth and continued cell cycles and cell growth, bypassing cell-cell contact inhibition similar to tumor cells. Lats1ΔN/ΔN MEFs produced tumors in nude mice after subcutaneous injection, although the tumor growth rate was much slower than that of ordinary cancer cells. Yap, a key transcriptional coactivator of the Hippo pathway, was overexpressed and stably retained in Lats1ΔN/ΔN MEFs in a cell density independent manner, and Lats2 mRNA expression was downregulated. In conclusion, N-terminally truncated Lats1 induced Lats2 downregulation and Yap protein accumulation, leading to chromosomal instability and tumorigenesis.
Materialart:
Online-Ressource
ISSN:
1477-9137
,
0021-9533
Sprache:
Englisch
Verlag:
The Company of Biologists
Publikationsdatum:
2013
ZDB Id:
219171-4
ZDB Id:
1483099-1
SSG:
12
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