Aberrant splicing of the DMP1‐ARF‐MDM2‐p53 pathway in cancer

Abstract

Alternative splicing of mRNA precursors is a ubiquitous mechanism for generating numerous transcripts with different activities from one genomic locus in mammalian cells. The gene products from a single locus can thus have similar, dominant-negative, or even opposing functions. Aberrant alternative splicing has been found in cancer to express proteins that promote cell growth, local invasion, and metastasis. This review will focus on the aberrant splicing of tumor suppressor/oncogenes that belong to the DMP1-ARF-MDM2-p53 pathway. Our recent study shows that the DMP1 locus generates both tumor-suppressive DMP1α (p53-dependent) and oncogenic DMP1β (p53-independent) splice variants, and the DMP1β/α ratio increases with neoplastic transformation of breast epithelial cells. This process is associated with high DMP1β protein expression and shorter survival of breast cancer (BC) patients. Accumulating pieces of evidence show that ARF is frequently inactivated by aberrant splicing in human cancers, demonstrating its involvement in human malignancies. Splice variants from the MDM2 locus promote cell growth in culture and accelerate tumorigenesis in vivo. Human cancers expressing these splice variants are associated with advanced stage/metastasis, and thus have negative clinical impacts. Although they lack most of the p53-binding domain, their activities are mostly dependent on p53 since they bind to wild type MDM2. The p53 locus produces splice isoforms that have either favorable (β/γ at the C-terminus) or negative impact (Δ40, Δ133 at the N-terminus) on patients' survival. Since the oncogenic alternative splicing products from these loci are expressed only in cancer cells, they may eventually become targets for molecular therapies.

Aberrant expression of ETS1 and ETS2 proteins in cancer

“…These observations suggested an oncogenic role of ETS1 in breast tumorigenesis (87). In contrast to ETS1 , loss of the Myb-like transcription factor DMP1α ( DMTF1α ) binds to the Ets site in the Arf promoter (91) is associated with low Ki67 and is associated with favorable prognosis (92) for Dmp1 original articles; 93–101; 67, 102–106 for reviews). Dmp1α also binds directly to p53 for activation in Arf -deficient cells (100, 101).…”

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

“…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.…”

“…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).…”

Clinical applications of mouse models for breast cancer engaging HER2/neu

“…Thus deregulation of HER2 leads to tumorigenesis. Aberrant overexpression of HER2 activates the Dmp1 promoter to stimulate the Arf-Mdm2-p53 self-autonomous tumor surveillance pathway through Pi3k-Akt-NF-κB and Ras-Raf-Mek-Erk-Jun cascades to eliminate incipient cancer cells by cell cycle arrest or apoptosis [10, 15, 57, 63]. …”