Abstract
Simple SummaryThe Dead-End (DND1) protein can interact with different messenger RNAs (mRNAs) in the cell. It uses multiple mechanisms to regulate expression of proteins from their cognate mRNAs. High levels of DND1 are found in the progenitor cells that develop into the egg and sperm. Here we review how and why defects in DND1 cause tumors in the testes and ovaries of vertebrates. Unexpectedly, some recent reports indicate that DND1 may also participate in human cancer development in cells other than those of the testes and ovaries. The goal of this review is to summarize the literature on the role of DND1 in cancers to obtain perspective regarding future scientific endeavors on DND1 function.The Ter mutation in Dead-End 1 (Dnd1), Dnd1Ter, which leads to a premature stop codon, has been determined to be the cause for primordial germ cell deficiency, accompanied with a high incidence of congenital testicular germ cell tumors (TGCTs) or teratomas in the 129/Sv-Ter mice. As an RNA-binding protein, DND1 can bind the 3′-untranslated region (3′-UTR) of mRNAs and function in translational regulation. DND1 can block microRNA (miRNA) access to the 3′-UTR of target mRNAs, thus inhibiting miRNA-mediated mRNA degradation and up-regulating translation or can also function to degrade or repress mRNAs. Other mechanisms of DND1 activity include promoting translation initiation and modifying target protein activity. Although Dnd1Ter mutation causes spontaneous TGCT only in male 129 mice, it can also cause ovarian teratomas in mice when combined with other genetic defects or cause germ cell teratomas in both genders in the WKY/Ztm rat strain. Furthermore, studies on human cell lines, patient cancer tissues, and the use of human cancer genome analysis indicate that DND1 may possess either tumor-suppressive or -promoting functions in a variety of somatic cancers. Here we review the involvement of DND1 in cancers, including what appears to be its emerging role in somatic cancers.
Highlights
The story of Dead-End 1 (DND1) in cancer of mouse germ cells can be traced back almost half a century
A new spontaneously arising mutation led to generation of the new inbred subline of mice (129/Sv-Ter) that exhibited primordial germ cell (PGC) deficiency, accompanied with a high incidence of congenital testicular germ cell tumors (TGCTs) or teratomas [1,2,3]
In Xenopus oocytes, Dnd1 was subject to ubiquitin-independent proteasomal degradation and translational repression, regulations that prevent premature accumulation of Dnd1 in oocytes [48]. These reports highlight the role of DND1 and its interactions with specific genetic susceptibility factors that result in germ cell tumors (TGCTs or OTs) in male and female animal model systems
Summary
The story of Dead-End 1 (DND1) in cancer of mouse germ cells can be traced back almost half a century. A new spontaneously arising mutation led to generation of the new inbred subline of mice (129/Sv-Ter) that exhibited primordial germ cell (PGC) deficiency, accompanied with a high incidence of congenital testicular germ cell tumors (TGCTs) or teratomas [1,2,3] These recessive phenotypes mapped to mouse chromosome 18, or the Ter locus [4,5]. Ter is due to a single nucleotide substitution occurring spontaneously in exon 3 of Dnd, which transforms the arginine residue at amino acid (aa) 190 into a premature stop codon, causing either truncation or loss of DND1 expression (Figure 1) This mutation results in the phenotypes of PGC loss, male and female sterility, and the high incidence of TGCT in males of the 129/Sv mice. AanPucabnMceerds.seAarPcuhbuMsiendg s“eDaNrcDh 1u”siansgth“eDkNeyDw1”oradswthaes ckoenydwuocrtdedw, washiccohnrdeutuctrende,dw12h1icrhesruelttusranseodf1Ju21nere2s0u2l1t.s Tahseosfe J1u2n1ep2a0p2e1r. sTwheesree 1m21anpuaaplelyrsswcrereenmedantouaidlleynsticfryeethneodsetothiadteanrteifyretlhatoesde tohatthearteopreilcaotefdthtois tphreetsoepnitcroevf itehwis. present review
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