Expression of the mad gene during cell differentiation in vivo and its inhibition of cell growth in vitro.

Västrik, Imre; Kaipainen, Arja; Penttilä, Tuula; Lymboussakis, A; Alitalo, Riitta; Parvinen, Martti; Alitalo, Kari

doi:10.1083/jcb.128.6.1197

Cited by 101 publications

(111 citation statements)

References 47 publications

(54 reference statements)

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“…In these two cell types, a switch from MYC ± MAX complexes to MAD1 ± MAX complexes upon di erentiation was observed. This change in the composition of MAX heterocomplexes is also likely to occur in other di erentiating cell types where the induction of Mad1, Mxi1, Mad3 and Mad4 has been documented (Zervos et al, 1993;Hurlin et al, 1994Hurlin et al, , 1995aLarsson et al, 1994;Chin et al, 1995;VaÈ strik et al, 1995). In light of these results, it has been postulated that the incorporation of MAD proteins into heterocomplexes with MAX may serve to downregulate genes activated by MYC ± MAX which are important for cell cycle progression.…”

Section: Introductionmentioning

confidence: 89%

Sequential expression of the MAD family of transcriptional repressors during differentiation and development

et al. 1998

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Members of the Myc proto-oncogene family encode transcription factors that function in multiple aspects of cell behavior, including proliferation, di erentiation, transformation and apoptosis. Recent studies have shown that MYC activities are modulated by a network of nuclear bHLH-Zip proteins. The MAX protein is at the center of this network in that it associates with MYC as well as with the family of MAD proteins: MAD1, MXI1, MAD3 and MAD4. Whereas MYC ± MAX complexes activate transcription, MAD ± MAX complexes repress transcription through identical E-box binding sites. MAD proteins therefore act as antagonists of MYC. Here we report the expression patterns of the Mad gene family in the adult and developing mouse. High level of Mad gene expression in the adult is limited to tissues that display constant renewal of di erentiated cell populations. In embryos, Mad transcripts are widely distributed with expression peaking during organogenesis at the onset of di erentiation. A detailed analysis of their pattern of expression during chrondrocyte and neuronal di erentiation in vivo, and during neuronal di erentiation of P19 cells in vitro, shows that Mad family genes are sequentially induced. Mad3 transcripts and proteins are detected in proliferating cells prior to di erentiation. Mxi1 and Mad4 transcripts are most abundant in cells that have further advanced along the di erentiation pathway, whereas Mad1 is primarily expressed late in di erentiation. Taken together, our data suggest that the di erent members of the MAD protein family exert their functions at distinct steps during the transition between proliferation and di erentiation.

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Section: Introductionmentioning

confidence: 89%

Sequential expression of the MAD family of transcriptional repressors during differentiation and development

et al. 1998

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“…Several studies have now demonstrated a generally inverse correlation between c-myc and Mad family member protein expression. For example, in some di erentiating hematopoietic cell lines, Mad1 is upregulated and is maximally expressed at a time when c-myc expression has ceased Larsson, et al, 1994;Vastrik et al, 1995). Mxi1 expression is similarly upregulated although not in all cell lines tested or with all di erentiation stimuli (Zervos et al, 1993;Larsson et al, 1994).…”

Section: Endogenous Mmip1 Expression and Co-immunoprecipitation With mentioning

confidence: 99%

“…Despite these associations, they are not absolute and clear exceptions exist. Thus, both Mad1 and Mxi1 may be expressed concurrently with c-myc in proliferating hematopoietic cells Zervos et al, 1993;Larsson et al, 1994;Vastrik et al, 1995) and c-myc expression has been reported in post-mitotic, di erentiated cells and tissues which express high levels of Mad genes (DePhino et al, 1991). Under such conditions, Mmip1 or related proteins could serve to neutralize the repressive activity of Mad members by reducing their ability to compete with c-myc for dimerization with Max.…”

Section: Endogenous Mmip1 Expression and Co-immunoprecipitation With mentioning

confidence: 99%

“…Although distinct patterns of tissue-speci®c expression have been demonstrated for Mad family members (Larson et al, 1994;Hurlin et al, 1995a;Vastrik et al, 1995), there is currently very little known about how they di er functionally. Indirect evidence suggesting unique roles for each protein has been provided by the observation that some carcinomas of the prostate, which karyotypically detectable loss of the MXI1 locus at 10q25 (Edelho et al, 1994;Shapiro et al, 1994Wechsler et al, 1994 harbor inactivating or missense mutations of the non-deleted allele (Eagle et al, 1995).…”

Section: Introductionmentioning

confidence: 99%

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Mmip1: a novel leucine zipper protein that reverses the suppressive effects of Mad family members on c-myc

et al. 1998

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C-myc, a member of the basic helix ± loop ± helix ± leucine zipper (bHLH-ZIP) protein family activates target genes in heterodimeric association with another bHLH-ZIP protein, Max. Max readily homodimerizes, competes with C-myc-Max heterodimers, and represses transcription. Four additional bHLH-ZIP proteins, Mad1, Mxi1, Mad3 and Mad4, heterodimerize with Max and also repress transcription of c-myc-responsive genes. We employed a yeast two-hybid approach to identify proteins which interact with Mxi. We identi®ed a novel ZIP-containing protein, Mmip1 (Mad memberinteracting protein 1) that strongly dimerizes with all four Mad members, but not with c-myc, Max, or with unrelated HLH proteins. The Mmip1-Mxi association is mediated by the ZIP domain of each polypeptide and is as strong or stronger than the associations between cmyc and Max or Max and Mxi1. In vitro, Mmip1 can inhibit DNA binding by Max-Mad heterodimers and, in vivo, can reverse the suppressive e ects of Mad proteins on c-myc functions. Mmip1 is found in a variety of cells types, is induced by serum stimulation, and can be coimmunoprecipitated from ®broblasts in association with Mxi1. By interfering with the dimerization between Max and Mad family member proteins, Mmip1 can indirectly up-regulate the transcriptional activity of c-myc and suppress the antiproliferative actions of Mad proteins.

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“…Some, such as Mad1 and Mad4, are expressed primarily in postmitotic, di erentiated cells in a pattern that correlates inversely with the presence of c-myc Larsson et al, 1994;Hurlin et al, 1995a;Vastrik et al, 1995). In contrast, other members, particularly Mxi1, are expressed by proliferating cells at quite high levels which change little during di erentiation (Zervos et al, 1993;Hurlin et al, 1995a;Larsson et al, 1994).…”

Section: Introductionmentioning

confidence: 99%

Lack of transcriptional repression by max homodimers

1998

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Max, a basic ± helix ± loop ± helix ± leucine zipper (bHLH-ZIP) protein, plays a central role in the transcriptional regulation of myc oncoprotein-responsive genes. Myc-max heterodimers bind to consensus E-box motifs near or within the promoters of these genes and activate gene expression, whereas heterodimers between max and members of the mad family of bHLH-ZIP proteins promote transcriptional repression. In contrast to all other members of the myc network, max readily homodimerizes and binds to identical E-box sites in vitro. However, the role for max homodimers in transcriptional repression in vivo is unclear. Upstream stimulatory factor (USF) is a bHLH-ZIP protein which does not interact with members of the myc-max-mad family. By replacing the HLH-ZIP domain of max with that from USF, we created a chimeric protein, max(USF), which was indistinguishable from max with respect to its ability to homodimerize and bind DNA. As expected, however, max(USF) was unable to heterodimerize with any of the tested max partner proteins and was incapable of suppressing c-myc target genes. Thus, transcriptional repression is an exclusive property of max-mad heterodimers and cannot be achieved by max homodimers alone.

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Expression of the mad gene during cell differentiation in vivo and its inhibition of cell growth in vitro.

Cited by 101 publications

References 47 publications

Sequential expression of the MAD family of transcriptional repressors during differentiation and development

Sequential expression of the MAD family of transcriptional repressors during differentiation and development

Mmip1: a novel leucine zipper protein that reverses the suppressive effects of Mad family members on c-myc

Lack of transcriptional repression by max homodimers

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