Cellular Biology

Checkpoints in the Cell Cycle are Implemented by Cyclins and Cyclin Dependent Kinases



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Cell growth and division is a highly regulated process that is known formally as the cell cycle.  Regulation of the cell cycle is the foundation of cancer research. By the most basic  definition,  cancer is a loss of control of the regulation of the cell cycle by cellular machinery.  For this reason, advances in knowledge of the cell cycle has led to many Nobel Prizes for those who have contributed. After a brief discussion of the terminology associated with description of cell cycle events, two historic landmarks in understanding cell cycle regulation will be discussed.

  When the cell is in its resting state, that is not growing or dividing, it is referred to as G0. (By tradition, G subscripted by a number 0). The cell, most typically receives an external signal that is transduced across the cell membrane by a chain, or pathway of interacting proteins. The result is that the cell is pushed into a state called G1. ( The G may be thought of growth, or gap, or in the case of G0, just G. It's best just to think of it as just  a state.  In G1 the cell prepares itself for the S, or DNA synthesis stage.  Synthesis or S stage is delayed by a checkpoint that is implemented with a system that contains the proteins cyclins and cyclin dependent kinases. A cyclin dependent kinase  (CDK) is an enzyme that can phosphorylate ( add a phosphate group) to a substrate only on the condition that it ( the CDK ) is bound to a cyclin. Thus cyclins are produced and destroyed during the evolution of the cell cycle. Cyclins, as indicated by their name, can be thought as the primary factor for driving the cell cycle through a checkpoint.

  If you are still here after that brief introduction to cyclins and cyclin dependent kinases, then I can conclude that you are here because of a classroom assignment or some overwhelming personal interest. In that case, you could spend 44 well spent minutes watching Paul Nurse give his Nobel Prize  acceptance lecture.

   In his lecture Paul begins by discussing his model organism, fission yeast. Fission yeast differs from more commonly used bakers yeast in that it divides into discrete cells after each cell division, where as bakers yeast forms filaments. Because fission yeast divides into discrete cells, it is relatively easy to identify cell division regulation mutants. Fission yeast has been a productive model organism in study of the cell cycle, and continues to be Paul Nurse's choice of model organism to the present day[1].

If fission yeast cells grow too large, they are presumed to be defective in mitotic ( cell division ) machinery,  and if they grow too small, they are defective in their checkpoint cellular machinery.  It is these small mutants that were the most interest to Paul.  He and his group named them the Wee mutants, Wee1 and Wee2, due to the influence of the local descriptive terminology. ( all the details are in the lecture )

  Thus began the long journey to discover the functioning details of the Wee mutants. Unlike bakers yeast, there were no molecular tools for working with fission yeast, so Paul and his group had to spend an entire year moving molecular tools from baker's yeast ( Saccharomyces cerevisiae ) to fission yeast (Schizosaccharomyces pombe). To completely give away the end to Paul's story, the Wee mutants were defective in cyclin dependent kinases.

    Ok, that really wasn't the end to his story. In fact there never really is an end,  Cell cycle regulation remains an open question at the basis of cancer research.  In any case, the next step was to extend the results for fission yeast to humans. To make a long story brutally short, Paul used a human DNA library, to rescue the Wee mutants. A DNA library is the chromosomal material from human cells chopped up into manageable segments using restriction enzymes. Members of  the resulting library, or group of restriction fragments, are inserted into samples of fission yeast using the previously mentioned molecular tools that were moved and developed for fission yeast. It was discovered that a particular fragment, and ultimately gene could "rescue" the Wee mutants and make them "happy" again. This was widely taken as proof that the same molecular checkpoints of the cell cycle extend to all eukaryotes, from yeast to humans.

  I previously promised two Nobel Prizes, but have decided to take a slight deviation. Alfred Knudson has been considered a long time Nobel candidate, and has been the recipient of the Albert Lasker award, considered by some to be "Americas Nobel".  Albert is widely known in the cancer research community for his "two hit" theory of cancer initiation. This theory came from the study of patterns of incidence of a type of cancer known as retinoblastoma.  Retinoblastoma is observed to have both an inhereted component and a random, or environmental component. Alfred theorized ( long before molecular tools were available) that there was a gene known as rb ( retinoblastoma ) that initiated a tumor due to loss of function.[2]. That is, those susceptible to the disease would inherit the gene in the heterozygous condition ( one active allele ) and when they lost function in that allele of the gene, a tumor would develop as a result of cells being null for that gene ( no function ). The gene was later cloned ( 1986 ) and determined to be a substrate for Paul Nurses' cyclin dependent kinases. In other words, rb is normally bound to, and inhibits a family of genes known as E2F. When rb is phosphorylated by a cyclin dependent kinase bound to a cyclin, it becomes unable to bind to E2F. Free E2F is a transcription factor that binds to DNA and initiates evolution through the cell cycle.

  Thus, when a cell is unable to produce active rb due to "hits" on both alleles, then E2F is always free and there will be no blocking by cyclins and CDKs at checkpoints.

   Thus, this is a good example of how scientists working on a problem from completely different angles can contribute to the ultimate construction of the underlying model. In this example,  an M.D. and Ph.D., Alfred Knudson began working on a particular cancer related problem in the late 1940's and predicted the existence of rb, and provided a general description of it's roll in regulation of the cell cycle. Later Paul Nurse, working on fission yeast, identified regulators of the cell cycle known as cyclin dependent kinases. When the scientific model was ultimately constructed, it was discovered that Knudson's rb was a phosphorylation target of Nurses's CDK's. Thus, the integrative process of data collection spanned quite a few decades to provide a basis to our current understanding of the cell cycle.

References

[1] Nurse P.    The cell cycle and beyond: an interview with Paul Nurse. Interview by Jim Smith  Dis Model Mech. 2009 Mar-Apr;2(3-4):113-5 [full text]

[2] Bob Kuska -Alfred Knudson: Two Hits Times 25 Years [Here]

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