In 1889, the American toymaker Charles Martin Crandall patented a then-novel board game called Pigs in Clover. It consisted of a large, circular labyrinth that players held in their hands and carefully tilted in one direction then another as a means to roll a colored marble from the clovered periphery, through a gated maze, and into the pigpen in the middle.
One hundred and twenty-five years and myriad iterations of the game later, generations of children have wiled away the hours seeing who can most often get their red and blue marbles all the way through their hand-held labyrinth. In theory, once two players are familiar with the game and develop comparable muscle memory, the outcome should be a wash. But what if one of the players learns to tilt the ball through a quicker alternative route? He could end up getting more balls in the target.
That roughly corresponds with one of the proposed scenarios when tissue-forming cells make a large, inactive precursor protein called dentin sialophosphoprotein (DSPP) within the tooth germ. The DSPP gets broken down into smaller, biologically active proteins called DPP and DSP. Like the marbles in the game, these two proteins pass through a labyrinth of processing pathways to reach their final destination in a soft extracellular protein matrix that will harden into dentin, the tooth’s mineralized core. Given their shared lineage, DPP and DSP should make it to their target in a one-to-one ratio. But DPP accounts for half of the non-collagenous protein in the dentin matrix, while DSP represents just 5 percent.
A possible explanation is DPP might be processed differently, allowing it to travel an alternate pathway out of the cell and into the extracellular matrix. Now in the February issue of the Journal of Dental Research, a team of NIDCR-supported scientists provides the first evidence that this is the case. They show that DPP is encoded in a region of the DSPP gene transcript, or mRNA, that contains a coding element called an internal ribosomal entry site, or IRES. A ribosome is the cellular organelle where proteins are synthesized, and an IRES helps to generate a signal within the ribosome for translation of the mRNA to begin in the middle, like starting to read the alphabet at the letter J instead of A.
This finding raised an interesting possibility. If conditions within a cell impair the normal cap-dependent translation of proteins that begins at the letter A, the alternate IRES-mediated signal would allow DPP to continue to be expressed.
But how then would the alternately expressed DPP exit the ribosome and cell? To get the answer, the scientists first confirmed in culture previous reports that, after assembly in the ribosome, DPP and DSP do indeed exist separately within the cell. They then made another key discovery. When translated via the IRES element, DPP lacks a short sorting sequence called a signal peptide that, like a barcode, helps to route newly synthesized proteins into the correct pathway for secretion out of the cell. Instead DPP is conveyed to the cell membrane aboard a bubble-like vesicle called an exosome. Given all of the above, the authors concluded that the alternate IRES translation mechanism could help to explain the disproportionate levels of DPP and DSP in the dentin matrix, information that could be helpful in understanding why some people have teeth with poorly formed dentin. More research, however, will be needed to sort out the details.
- The paper is titled “DSPP Contains an IRES Element Responsible for the Translation of Dentin Phosphophoryn.” It is published in the February issue of the Journal of Dental Research. The authors are Y. Zhang, Y. Song, S. Ravindran, Q. Gao, C.C. Huang, A. Ramachandran, A. Kulkarni, and A. George.
 In the name of accuracy, DSPP precursor also yields a third protein, known by the acronym DGP. Little has been published on DGP, and most discussions of DSPP center on DPP and DSP. Thus, the omission.