DMP1β , a splice isoform of the tumour suppressor DMP1 locus, induces proliferation and progression of breast cancer

Inoue

2018

Cancer Rep Rev

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The ETS transcription factors regulate expression of genes involved in normal cell development, proliferation, differentiation, angiogenesis, and apoptosis, consisting of 28 family members in humans. Dysregulation of these transcription factors facilitates cell proliferation in cancers, and several members participate in invasion and metastasis by activating gene transcription. ETS1 and ETS2 are the founding members of the ETS family and regulate transcription by binding to ETS sequences. They are both involved in oncogenesis and tumor suppression depending on the biological situations used. The essential roles of ETS proteins in human telomere maintenance have been suggested, which have been linked to creation of new Ets binding sites. Recently, preferential binding of ETS2 to gain-of-function mutant p53 and ETS1 to wild type p53 (WTp53) has been suggested, raising the tumor promoting role for the former and tumor suppressive role for the latter. The oncogenic and tumor suppressive functions of ETS1 and 2 proteins have been discussed.

Section: Ets1 and Ets2mentioning

confidence: 99%

Aberrant expression of ETS1 and ETS2 proteins in cancer

Inoue

2018

Cancer Rep Rev

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“…The human DMP1 ( DMTF1 ) locus encodes two other splice variants, DMP1β and DMP1γ. We recently reported that DMP1β accelerates G1-S progression and contributes mammary carcinogenesis in vivo (51). On the other hand, the biology of DMP1γ in cell proliferation, apoptosis, and/or tumorigenesis is currently unknown.…”

Section: Discussionmentioning

confidence: 99%

“…Our study shows that DMP1β does not bind to p53 (data not shown); whether or not DMP1γ binds to p53 has not been studied. It is very likely that they DMP1γ does not affect the function of p53 because i) it lacks the 2 nd and 3 rd Myb-like domain required for the physical interaction with p53 (52), and ii) DMP1β accelerated the proliferation breast cancer cells independent of p53 (51). To date 40 splice variants have been reported from the hDMP1 locus (89), but only two of them -aAug10 (hDMP1α) and bAUG10 (a variant that lacks the amino-terminal 88 amino acids) encode proteins that can bind to p53.…”

Section: Discussionmentioning

confidence: 99%

“…We recently reported that Dmp1 physically interacts with p53 to neutralize the known functions of Mdm2 (or HDM2), namely ubiquitination, nuclear-cytoplasmic transport, and suppression of transport (47), a very unique property among p53/Mdm2-binding transcription factors (48). The h DMP1 locus encodes at least three splicing variants -h DMP1α, β, and γ with antagonizing functions (49–51, reviewed in 52). The h DMP1α gene corresponds to murine Dmp1α that positively regulates the p19 Arf -p53 pathway (761 amino acids [a.a.] in mice, 760 a.a. in humans).…”

Section: Introductionmentioning

confidence: 99%

“…Conversely, the hDMP1β (272 a.a.) and γ (285 a.a.) isoforms lack the DNA-binding domain, and hDMP1β is dominant-negative over hDMP1α in CD13 and ARF induction (49, 50). Our recent study showed that forced expression of hDMP1β stimulates cell proliferation in p53-independent fashion and induces aberrant growth of mammary glands and accelerates tumorigenesis (51). …”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Stabilization of the p53-DNA Complex by the Nuclear Protein Dmp1α

Kendig

Kai

et al. 2017

Cancer Investigation

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We recently reported the existence of a physical interaction between the Myb-like transcription factor Dmp1 (Dmtf1) and p53 in which Dmp1 antagonized polyubiquitination of p53 by Mdm2 and promoted its nuclear localization. Dmp1 significantly stabilized p53-DNA complexes on promoters that contained p53-consensus sequences, which were either supershifted or disrupted with antibodies to Dmp1. Lysates from mice injected with doxorubicin showed that Dmp1 bound to p21Cip1, Bbc3, and Thbs1 gene regulatory regions in a p53-dependent fashion. Our data suggest that acceleration of DNA-binding of p53 by Dmp1 is a critical process for Dmp1 to increase the p53 function in Arf-deficient cells.

Transcription factors that interact with p53 and Mdm2

Inoue

Frazier

2015

Intl Journal of Cancer

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The tumor suppressor p53 is activated upon cellular stresses such as DNA damage, oncogene activation, hypoxia, which transactivates sets of genes that induce DNA repair, cell cycle arrest, apoptosis, or autophagy, playing crucial roles in the prevention of tumor formation. The central regulator of the p53 pathway is Mdm2 which inhibits transcriptional activity, nuclear localization, and protein stability. More than 30 cellular p53-binding proteins have been isolated and characterized including Mdm2, Mdm4, p300, BRCA1/2, ATM, ABL, and 53BP-1/2. Most of them are nuclear proteins; however, not much is known about p53-binding transcription factors. In this review, we focus on transcription factors that directly interact with p53/Mdm2 through direct binding including Dmp1, E2F1, YB-1, and YY1. Dmp1 and YB-1 bind only to p53 while E2F1 and YY1 bind to both p53 and Mdm2. Dmp1 has been shown to bind to p53 and block all the known functions for Mdm2 on p53 inhibition, providing a secondary mechanism for tumor suppression in Arf-null cells. Although E2F1-p53 binding provides a checkpoint mechanism to silence hyperactive E2F1, YB-1 or YY1 interaction with p53 subverts the activity of p53, contributing to cell cycle progression and tumorigenesis. Thus, the modes and consequences for each protein-protein interaction vary from the viewpoint of tumor development and suppression.