Rubinsteintaybi Syndrome

Another mental retardation syndrome associated with the PKA/ERK/CREB pathway is Rubinstein-Taybi Syndrome (RTS). RTS patients have some facial abnormalities, broad big toes and thumbs, and mental retardation. The RTS gene has been mapped to chromosome 16 and identified as CREB Binding Protein (CBP). As described earlier, CBP is a transcriptional co-activator with CREB that obligatorily participates with phospho-CREB to regulate gene expression downstream of the CRE (20). CBP is a Histone Acetyl Transferase (HAT), and one mechanism through which CBP promotes gene expression is histone acetylation, which promotes exposure of DNA for transcription. CBP's loss of this HAT function likely is one important contributing factor in RTS, through derangements of the normal mechanisms controlling CREB-mediated gene expression. A partial knockout mouse model in which CBP activity is lost also exhibits learning deficiencies (20), which is similar to several other mental retardation syndromes that are highlighted in this chapter (see Table 1).

same cascade has been implicated in learning and memory in a wide variety of different species—it is now safe in my opinion to add the human to the list.

It also is interesting to speculate about another potential downstream target of the ERK cascade, the protein synthesis machinery (see Figure 1). This target is appealing given the widespread documentation that we have discussed concerning a role for protein synthesis in learning. As was described in Chapter 7, ERK is known to regulate protein synthesis by regulating the activity of eIF4E via the intervening kinase mnk. Also, a known role for RSK2, the Coffin-Lowry Syndrome gene product, is regulation of protein synthesis. It is intriguing to consider protein synthesis as a potential target downstream of the gene products for Neurofibromatosis and Coffin-Lowry Syndrome because the Fragile X Mental Retardation type 1 (FMR1) gene product (FMRP) likely contributes to regulating protein synthesis as well (14); we will discuss this in Section III. This potentially would tie yet a third human mental retardation gene product, the Fragile X Protein, into a common signaling/regulatory cascade.

It is notable that no mutation in any of the core signaling components of the ras/ERK cascade (ras, raf, mek, and ERK) has been identified as linked to human learning disorders to date. I think that it is unlikely that this will ever be the case because, as we have already discussed, the role of these enzymes is in no way limited to learning and memory—this pathway was discovered as one of the core signaling components controlling cell division. Loss of the core signal transduction cascade quite likely could result in cellular lethality. Mutations in modulators of the ras/ERK cascade such as NF1, of course, can lead to viable animals. In the specific case of the neurofibromatosis gene, the gene was initially discovered as an oncogene, which when mutated leads to uncontrolled cell division in specific cells. Subsequent work led to the discovery of its role in regulating ras-dependent processes, which is, of course, consistent with the fundamental role of the ras/ERK cascade in regulating cell division.

In thinking about these disparate roles of the ras/ERK cascade in both learning and cell division, it is interesting to consider that in the early 1970s President Nixon declared a "war on cancer", which in part led to increased cancer funding and great progress in understanding the regulation of mammalian cell division. Also, a great number of oncogenes were discovered in this era, which were named for the cancers with which they are associated. If Nixon had instead declared a "war on mental retardation," I find it interesting to think that cancer biologists might now be scratching their heads, wondering what all these learning-related genes were doing regulating cell division.

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