MadSci Network: Biochemistry

Re: Could you please describe a further example of a positive feedback system

Date: Mon Aug 23 19:39:11 2004
Posted By: Steve Mack, Post-doc/Fellow, Molecular and Cell Biology
Area of science: Biochemistry
ID: 1093197149.Bc

Hi Lizz,

There are many examples of positive feedback (aka feed-forward) systems at work in biological systems. Unlike negative feedback (or feedback inhibition) systems, where the presence of a product of the system results in a decrease in the production of that product, in positive feedback systems the presence of a product (or signal) results in an increase in the production (amplification) of that product (or signal).

Looking at it this way, you can see that the best example of a positive feedback system is life itself. Under the correct conditions, a living organism (the "product" of metabolism) will make more copies of itself. In addition, when populations are increasing exponentially, they are exerting positive feedback on their growth rate; the larger a population is, the faster it will grow (until it uses all of the available resources). I know, this answer might seem a bit glib, because you probably want examples of enzyme systems that are regulated by positive feedback, but keep it in mind for later.

On the sub-cellular level, there are plenty of examples of positive feedback regulation. Take for example a transcriptional activator protein that promotes the expression of the gene that encodes that same protein. The presence of the activating protein will result in the transcription of mRNA, which will be translated into additional transcriptional activator proteins, which will activate the transcription of more mRNA. It looks like such a mechanism is at work in the transcription of the p53 and Zac-1 proteins, two proteins in the apoptosis (aka programmed cellular death) pathway. I am not going to go into the gory specifics here, but you can read the paper (236 kb PDF) by Rozenfeld-Granot, et al describing how they determined that Zac-1 activates p53, which is a transcriptional activator that stimulates the transcription of Zac-1 (among many other genes) and the synthesis of more Zac-1 protein, which can activate more p53.

Another example is the lexA, recA system in the bacterial SOS response. LexA is a repressor protein that down-regulates the transcription of SOS proteins like recA. However, when the cell is damaged, recA can bind to single-stranded DNA and cleave the lexA repressor, which results in the expression of the recA gene and the synthesis of more recA protein.

There are also non-transcriptional, protein-based positive feedback systems at work, as in the case of digestive enzymes like pepsin. Pepsin is a potent protease; as such, it is dangerous for a cell to make active pepsin, because it could be digested by the enzyme, so pepsin is made in an inactive form, pepsinogen. Pepsinogen is activated in very acidic environments (like the stomach) by self-cleaving (auto-catalysis) its 44 amino terminal-most residues, generating an active pepsin molecule. One pepsin molecule can activate more, by cleaving the n-terminal 44 amino acids of other pepsiongen molecules, leading to a cascade of rapid pepsin activation.

Hormone responses also involve positive feedback systems. In childbirth, uterine contractions are stimulated by the hormone oxytocin, moving the baby toward the cervix. Pressure sensors in the cervix send signals to the brain, telling it to release more oxytocin, which stimulates the uterus to push harder. This increases the pressure on the cervix, which increases the strength of the contractions, until the baby is born, after which the pressure stimuli stop, and the level of oxytocin drops off.

Growth of the prostate gland is also regulated in a postive feedback system. Prostate growth is stimulated by the presence of the hormone dihydrotestosterone (DHT), which is synthesized by the steroid 5-alpha- reductase enzyme. The synthesis of 5-alpha-reductase in the prostate is up-regulated by the presence of DHT, so that DHT results in the production of more DHT in the prostate gland.

In fact, many people make the argument that the development of an organism form a zygote depends on positive feedback regulation. As you can see from some of the examples I have provided here, positive feedback can result in a dramatic state-change in a system. The induction of the SOS response, apoptosis, the activation of a whole population of digestive enzymes, childbirth, and the growth of an organ are all examples where the status quo changes dramatically as the result of the amplification of a small signal. This is what has to happen when a embryo develops into an organism; as the embryo develops, different cells are likely "pushed" to different extremes of structure and function through the action of various positive feedback loops, resulting in the differentiation of cells into distinct tissues.

In addition to nice things, like developing from an embryo into a full grown mad scientist, positive feedback can also lead to some diseases as a result of the disruptions of normal cell function. One example is cancer, where a few initial "insults" to the cell (mutations in a few proto-oncogenes and tumor suppressor genes) can progress to damaged cells that accumulate mutations and proceed to grow out of control. This is positive feedback in both the accumulation of DNA damage and in cellular growth and replication. Remember my original, glib answer about life being an example of positive feedback? Well the same thing is going on with cancer cells; unchecked growth that accelerates with population size.

Yet another example of diseases that result from postive feedback are the spongiform encephalopathies (SE), like Bovine SE (aka Mad Cow Disease). In these dieases, a prion (an improperly folded version of a protein known as PrP) catalyzes the improper folding of other PrP proteins in the brain, generating new prions. These new prions can catalyze the change in other PrP proteins, similar in effect to pepsin catalyzing the formation of more pepsin from pepsinogen. This leads to the formation of long chains of these prion proteins, holes in the brain, disease and eventually death. A similar process (progressive improper folding of the amyloid beta protein) may be at work in the progression of amyloid plaques in Alzheimers disease as well.

So I hope that those examples prove useful for you. You can find out much more about some of these in a college-level Biochemistry textbook, or a Medical Biochemistry textbook. I recommend Biochemistry by L. Stryer, and the Textbook of Biochemistry with Clinical Correlations editted by Thomas M. Devlin.

I've also provided some references (below) that you might want to review.

Rozenfeld-Granot G, Krishnamurthy J, Kannan K, Toren A, Amariglio N, Givol D, Rechavi G. (2002) A positive feedback mechanism in the transcriptional activation of Apaf-1 by p53 and the coactivator Zac-1. Oncogene. 21:1469-76.

FW George, DW Russell, and JD Wilson (1991) Feed-forward control of prostate growth: dihydrotestosterone induces expression of its own biosynthetic enzyme, steroid 5 alpha- reductase. Proc Natl Acad Sci U S A. 88: 80448047.

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