Transcription factor JunD, deprived of menin, switches from growth suppressor to growth promoter.
Different components of the AP1 transcription factor complex appear to have distinct effects on cell proliferation and transformation. In contrast to other AP1 components, JunD has been shown to inhibit cell proliferation. Also, in prior studies, JunD alone bound menin, product of the MEN1 tumor suppressor gene, and JunD's transcriptional activity was inhibited by menin, suggesting that JunD might achieve all or most of its unique properties through binding to menin. Analyses of JunD and menin effects on proliferation, morphology, and cyclin D1 in stable cell lines unmasked an unexpected growth promoting activity of JunD. Whereas stable overexpression of wild-type (wt) mouse JunD in JunD-/- immortalized fibroblasts inhibited their proliferation and reverted their transformed-like phenotype, overexpression of a missense mouse JunD mutant (mJunDG42E) with disabled binding to menin showed opposite or growth promoting effects. Similarly, stable overexpression of wt mouse JunD in wt immortalized fibroblasts inhibited growth. In contrast, its overexpression in Men1-/- immortalized fibroblasts enhanced their already transformed-like characteristics. To conclude, JunD changed from growth suppressor to growth promoter when its binding to menin was prevented by a JunD mutant unable to bind menin or by Men1-null genetic background.
Agarwal
Sunita K
SK
Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA. sunitaa@intra.niddk.nih.gov
Novotny
Elizabeth A
EA
Crabtree
Judy S
JS
Weitzman
Jonathan B
JB
Yaniv
Moshe
M
Burns
A Lee
AL
Chandrasekharappa
Settara C
SC
Collins
Francis S
FS
Spiegel
Allen M
AM
Marx
Stephen J
SJ
D000818:Animals; D001483:Base Sequence; D015153:Blotting, Western; D002455:Cell Division; D002460:Cell Line; D019938:Cyclin D1 / Q000378:metabolism; D017931:DNA Primers; D051379:Mice; D009363:Neoplasm Proteins / Q000378:metabolism*; D009374:Neoplasms, Experimental / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism*
D017931:DNA Primers; C105373:MEN1 protein, human; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; D016755:Proto-Oncogene Proteins c-jun; D019938:Cyclin D1