Function of the c-Myc antagonist mad1 during a molecular switch from proliferation to differentiation

被引:65
作者
Cultraro, CM
Bino, T
Segal, S
机构
[1] NCI,NAVY MED ONCOL BRANCH,NIH,BETHESDA,MD 20889
[2] UNIFORMED SERV UNIV HLTH SCI,BETHESDA,MD 20889
关键词
D O I
10.1128/MCB.17.5.2353
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Mad-Max heterodimers have been shown to antagonize Myc transforming activity by a mechanism requiring multiple protein-protein and protein-DNA interactions. However, the mechanism by which Mad functions in differentiation is unknown. Here, we present evidence that Mad functions by an active repression mechanism to antagonize the growth-promoting function(s) of Myc and bring about a transition from cellular proliferation to differentiation. We demonstrate that exogenously expressed c-Myc blocks inducer-mediated differentiation of murine erythroleukemia cells without disrupting the induction of endogenous Mad; rather, high levels of c-Myc prevent a heterocomplex switch from growth-promoting Myc-Max to growth-inhibitory Mad-Max. Cotransfection of a constitutive c-myc with a zinc-inducible madl results in clones expressing both genes, whereby a switch from proliferation to differentiation can be modulated. Whereas cells grown in N'N'-hexamethylene bisacetamide in the absence of zinc fail to differentiate, addition of zinc up-regulates Mad expression by severalfold and differentiation proceeds normally. Coimmunoprecipitation analysis reveals that Mad-Max complexes are in excess of Myc-Max in these cotransfectants. Moreover, we show that the Sin-binding, basic region, and leucine zipper motifs are required for Mad to function during a molecular switch from proliferation to differentiation.
引用
收藏
页码:2353 / 2359
页数:7
相关论文
共 50 条
[41]   Expression of Mad1 protein inhibits proliferation of cancer cells and inversely correlated with Myc protein expression in primary gastric cancer [J].
Han, S ;
Park, K ;
Kim, HY ;
Lee, MS ;
Kim, HJ ;
Kim, YD .
ONCOLOGY REPORTS, 1999, 6 (03) :569-574
[42]   The c-MYC NHE III1: Function and Regulation [J].
Gonzalez, Veronica ;
Hurley, Laurence H. .
ANNUAL REVIEW OF PHARMACOLOGY AND TOXICOLOGY, 2010, 50 :111-129
[43]   Comparative analysis of the structure and function of the chicken c-myc and v-myc genes: v-myc is a more potent inducer of cell proliferation and apoptosis than c-myc [J].
Petropoulos, CJ ;
Givol, I ;
Hughes, SH .
ONCOGENE, 1996, 12 (12) :2611-2621
[44]   Gfi1 upregulates c-Myc expression and promotes c-Myc-driven cell proliferation [J].
Yangyang Zhang ;
Fan Dong .
Scientific Reports, 10
[45]   Gfi1 Upregulates c-Myc Expression and Promotes c-Myc-Driven Cell Proliferation [J].
Zhang, Yangyang ;
Dong, Fan .
BLOOD, 2019, 134
[46]   Gfi1 upregulates c-Myc expression and promotes c-Myc-driven cell proliferation [J].
Zhang, Yangyang ;
Dong, Fan .
SCIENTIFIC REPORTS, 2020, 10 (01)
[47]   Expression of the c-Myc antagonists Mxi 1, Mad 1, and Mad 4 following in vitro luteinization of primate granulosa cells. [J].
Chaffin, CL .
BIOLOGY OF REPRODUCTION, 2001, 64 :164-164
[48]   A SWITCH FROM MYC-MAX TO MAD-MAX HETEROCOMPLEXES ACCOMPANIES MONOCYTE/MACROPHAGE DIFFERENTIATION [J].
AYER, DE ;
EISENMAN, RN .
GENES & DEVELOPMENT, 1993, 7 (11) :2110-2119
[49]   MAD3 AND MAD4 - NOVEL MAX-INTERACTING TRANSCRIPTIONAL REPRESSORS THAT SUPPRESS C-MYC DEPENDENT TRANSFORMATION AND ARE EXPRESSED DURING NEURAL AND EPIDERMAL DIFFERENTIATION [J].
HURLIN, PJ ;
QUEVA, C ;
KOSKINEN, PJ ;
STEINGRIMSSON, E ;
AYER, DE ;
COPELAND, NG ;
JENKINS, NA ;
EISENMAN, RN .
EMBO JOURNAL, 1995, 14 (22) :5646-5659
[50]   c-MYC delays prometaphase by direct transactivation of MAD2 and BubR1 [J].
Menssen, Antje ;
Epanchintsev, Alexey ;
Lodygin, Dmitri ;
Rezaei, Nousin ;
Jung, Peter ;
Verdoodt, Berlinda ;
Diebold, Joachim ;
Hermeking, Heiko .
CELL CYCLE, 2007, 6 (03) :339-352