BSCB Science Writing Prize 2009

To Ub or not to Ub: how a cell manages its resources | Back

By Sebastian Hayes, Department of Physiology, University of Liverpool

Picture the proteins or enzymes that exist within a cell as the people that make up a society: the workhorses, the messengers, and even the governors of this microscopic world all working together in a tight, highly regulated network.  In a cell’s lifetime, it will require a complex mixture of a whole host of proteins to perform specific functions.  Just as in the Chinese Great Leap Forward a predominantly agrarian workforce was turned to steel production, so a cell can respond to external stimuli to reallocate resources from normal “resting” conditions to whatever is required.  However, just as in this historical example, there are occasions when this societal redistribution is ill-advised and the effects can be devastating.

Most enzymes have a short half-life, as they are degraded soon after synthesis and their stores are replenished by newly synthesised proteins[1].  This state is advantageous for a cell as it allows for quick responsiveness to environmental pressures.  Once a protein has been degraded, the constituents that it was composed of can be reused to synthesise new proteins.  Indeed, cells within a human body are in a constant state of flux, cycling through phases that require different levels of specific enzymes.

Proteins in the cell are predominantly broken down by a large degradative machine called the proteasome[2].  In isolation, the proteasome appears to be unselective towards its targets, therefore a cell needs to make sure that only selected proteins are degraded in a controlled spatio-temporal fashion.   To do this, the cell has evolved a complex mechanism that relies on the ubiquitously expressed molecular tag aptly (although maybe not particularly imaginatively) called ubiquitin (Ub).  Ubiquitin is tagged onto proteins by a group of enzymes known as E3 Ligases and this results in their recognition by the proteasome.  Ubiquitination, however, is reversible, and through the action of a class of enzymes known as deubiquitinating enzymes (DUBs) tagged proteins can be rescued from their fate. This process has to be highly regulated, as the deregulated depletion or the extended lifespan of a critical enzyme could be extremely adverse.

Let us take as an example the case of a well-studied pathway involving an E3 Ligase called MDM2, a DUB called USP7, and a very popular protein known as p53, the “Guardian of the Genome” (see figure 1).  p53 is what is known as a tumour suppressor, because it protects cells from developing the sort of mutations that can result in the transformation from a normal to a tumourogenic state.  p53 is quickly degraded under normal cellular conditions due to its tight association with MDM2, which bestows p53 with the “kiss of death” that is ubiquitin and targets it for degradation by the proteasome[3].  However, under conditions of cellular stress, when the DNA in our cells (the genome) is prone to acquiring mutations, cellular levels of p53 are increased as it is no longer being degraded and can be found in an active form.  This allows it to carry out its function and protect the genome by stalling cells until they have repaired the damage or, if the damage is irreparable, shutting them down by inducing programmed cell death so that the mutations cannot be passed on any further by cell division.  It is believed that one of the enzymes responsible of this switch from degrading to non-degrading is the DUB USP7, which removes ubiquitin from p53 and thereby rescues it from the proteasome.  The plot thickened however, when scientists discovered that USP7 also deubiquitinates MDM2, and also rescues it from proteasomal degradation.  Therefore, USP7 rescues both the enzyme responsible for target degradation (MDM2) and the target itself (p53). The picture we are left with is that of a complex molecular dance which must be regulated on a range of levels to suit every kind of cellular context, which may be expected given the importance of this pathway in the maintenance of healthy cells.  Indeed, mutations in any of the members of the described molecular ménage à trois would lead to a susceptibility to further mutations which could be passed on from cell to cell and eventually lead to tumour formation.  It may therefore not come as a surprise that mutations in the p53 gene are found in over 50 percent of human cancers, and up to 80 percent of cancers of the blood such as leukaemia[4].  The discovery of how these proteins work together under normal physiological conditions and the aberrations that occur during cancer has lead many in the field to actively pursue the identification of chemical compounds that can modulate the functions and interactions between these proteins as these compounds could potentially be used as a therapeutic strategy to treat cancer.

The ubiquitin field is expanding exponentially since its inception in the 1980s[5].  Ubiquitination is important in almost all cellular processes and regulates the functions of a plethora of enzymes.  This essay highlights one of the better-studied models of how ubiquitin can control the functions of particular enzymes.  Deregulation of ubiquitination can lead to all sorts of diseases ranging from cancers to neurodegenerative disorders to diabetes.  The pharmaceutical industry has its ears pricked for new developments in the basic understanding of how ubiquitin controls cellular events as the elucidation of the tug of war between degradation and its evasion has brought about the idea that whoever can control this in an enzyme-specific manner holds the key to a silver bullet that could be the answer to a specific pathology.  Whether you are a cell biologist or his will not be the last time the word ubiquitin will appear on your radar.

1. Pickart CM. FASEB J. 1997 Nov;11(13):1055-66.
2. Ciechanover A. Cell Death Differ. 2005 Sep;12(9):1178-90.
3. Brooks CL, Gu W. Cell Cycle. 2004 Jul;3(7):895-9.
4. Secchiero P, di Iasio MG, Gonelli A, Zauli G. Curr Pharm Des. 2008;14(21):2100-10.
5. Wilkinson KD. Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15280-2.