Functional interaction between tumor suppressor menin and activator of S-phase kinase.
Multiple endocrine neoplasia type I (MEN1), a hereditary tumor syndrome, is characterized by the development of tumors in multiple endocrine organs. The gene mutated in MEN1 patients, Men1, encodes a tumor suppressor, menin. Overexpression of menin leads to inhibition of Ras-transformed cells. However, it is unclear whether menin is essential for repression of cell proliferation, and if it is, how it inhibits cell proliferation. Here, we show that targeted disruption of the Men1 gene leads to enhanced cell proliferation, whereas complementation of menin-null cells with menin reduces cell proliferation. Moreover, menin interacts with activator of S-phase kinase (ASK), a component of the Cdc7/ASK kinase complex that is crucial for cell proliferation, but does not appear to alter Cdc7 kinase activity in in vitro kinase assays. We identify the COOH terminus of menin as the domain that mediates the specific interaction with ASK. Notably, wild-type menin completely represses ASK-induced cell proliferation, although it does not obviously affect the steady-state cell cycle profile of ASK-infected cells. Interestingly, disease-related COOH-terminal menin mutants that do not interact with ASK completely fail to repress ASK-induced cell proliferation. Together, these findings demonstrate a functional link between menin and ASK in the regulation of cell proliferation.
Schnepp
Robert W
RW
Abramson Family Cancer Research Institute, Department of Cancer Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6160, USA.
Hou
Zhaoyuan
Z
Wang
Haoren
H
Petersen
Clark
C
Silva
Albert
A
Masai
Hisao
H
Hua
Xianxin
X
D002453:Cell Cycle / Q000235:genetics; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D002455:Cell Division / Q000502:physiology; D002478:Cells, Cultured; D006801:Humans; D018761:Multiple Endocrine Neoplasia Type 1 / Q000235:genetics; D009154:Mutation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D021122:Protein Subunits; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
D018797:Cell Cycle Proteins; C485678:DBF4 protein, human; C105373:MEN1 protein, human; D021122:Protein Subunits; D011518:Proto-Oncogene Proteins; C068619:CDC7 protein, human; C489403:Cdc7 protein, mouse; D017346:Protein Serine-Threonine Kinases