Category Archives: Cell physiology

BRCA1 – a new role

DNA repair, In General, Replication

Mutations in the breast tumor risk gene (BRCA1) make individual susceptible to tumors not only of breasts and ovar, but of many different origins. This is due to the role of BRCA1 in the DNA repair  mechanisms.

A paper in Molecular Cell shows now an additional role for BRCA1: It is involved when the replication fork gets stuck at an interstrand cross which is likely to occur in the presence of the drug Cisplatin. With the help of BRCA1 the CMG helicases, which unwinds the strand to be replicated, are unloaded. Then DNA can be repaired and finally replicated faithfully.

Nicely done.

Clock gene necessary for implantation

Circadian Clock, Endocrinology, Steroidogenesis

Endocrinologists are aware of the circadian clock since it determines the release of many hormone likewise cortisol in a daily rhythm. There are other rhythmic hormone releases not dependent on the circadian clock, for example the prolactin release in a circannual fashion, or faster pulses for hormones of the pituitary with one to three hours pulse lengths.

In short, the circadion clock is found in the supraoptic nucleus of the hypothalamus and concists of the RNAs and proteins Per, BMAL, Clock, and cryptochrome(s). These are generated and inactivated in a way that autonomously repeats about every 24 hours. It can also adjust to a light-dark cycle.

What is new in a paper by Liu et al. from the Bradfield labaratory at the Univ. of Wisconsin in PNAS is that steroidogenesis — the synthesis of steroids –is coupled to the clock protein BMAL-1. They show that female mice which fail to express the BMAL protein in steroidogenic cells are not capable to implant an fertilized egg into the uterus and fail to generate progeny. When they transplant one normal uterus into these animals  by exchanging one defective with the normal one, these mice will again produce offspring. The defect can, in addition, be rescued by soluble progesterone which shows that progesterone is a determining factor in nidation/implantation.

These experiments are nicely done. The conclusion, however, that  the hormone production in the ovar is decisive is too far fetched: They have eliminated the entire steroidogenesis in these mice,  therefore the only hormone producing organ of the rescued animals is the transplanted normal ovar. Progestone or other steroid hormones being soluble and acting far away from their place of synthesis could under normal conditions be generated in the adrenal or somewhere else as well. The ovar is by far not the only organ with progesterone synthesis. It will be difficult to answer the question whether the ovar’s progesterone synthesis is required for implantation, since a block in the progesteron synthesis will likely block androgen, estrogen and corticoid synthesis. You would need the 3ß-hydroxysteroid dehydrogenase 1 inactive only in the ovar. And still the animal needs androstendione substitution to allow ongoing testosterone and estrone and thus estradiol synthesis.

Worth to read!

At least a bacterial ligand for the ArH

Bacteria, Cell physiology, Immunology, Innate defense, Tuberculosis, ,

The aryl hydrocarbon receptor ArH is a nuclear receptor and as such a transcription factor which has been shown to be activated by dioxins and other environmental toxins. Upon ligand binding it is translocated to the nucleus, binds dioxin responsive elements on the DNA, and triggers gene activation notably of CYP 1 monoxygenases, which in turn degradate dioxins to more soluble compounds thus facilitating their removal. It not only binds dioxins, but polyaromatic substances like benzopyrenes in tobacco smoke and a variety of plant substances like e.g. indigo.

Its structure as basic helix loop helix (bHLH) protein has been determined.

It has been questionable how a molecule with such a ligand profile has survived evolution. Groups from Berlin have now determined bacterial secondary products as ligands of the receptor, too. In a paper in Nature this week they describe Pseudomonas aeruginosa phenazines and Mycobacterium tuberculosis phthiols as ligands which activate anti-bacterial responses in mice. This role makes much more sense in terms of evolution. It would be more beneficial to have the protein than not to have it. Nicely done.

Review on stem cells for treating diseases

Cell physiology, Drug, Immunology, ,

This weeks Science features a review (DOI: 10.1126/science.1247391) on induced Pluripotent Stem Cells (PSC) and the treatment of diseases with their help. The disease treated in the paper are hematopoietic maladies, diabetes mellitus, liver diseases, neurological disorders,  muscular distrophy and heart diseases.

I was particular interested in diabetes and went to study the article. I was surprised to see that a paper was mentioned where immunotherapy, especially the induction of tolerance, was tried. I have explained the strategy behind in a separate article on this website.

The article, at least for the diabetes part, is highly instructive. You may find it in an University library.

The Proteasome adaptive response

Biochemistry, Cell physiology, ,

While you are most probably familiar with proteasomes (otherwise it is barrel-like structure with heptameric symmetry of four ring, holes at both end through which ubiquitin targets proteins to be digested during which process it produces peptides of seven to nine amino acids which are either digested or loaded into the peptide pockets of histocompatibility proteins) you would not have thought about how proteasomes themselves are regulated.  A free article in Molecular Cell (dx.doi.org/10.1016/j.molcel.2014.06.017) demonstrates that a protein Adc17 is induced in stress and helps to maintain adequate numbers of proteasomes. A nice piece of work!

GABA receptor structure revealed

Biochemistry, Brain, Cell physiology, Neurotransmitters

GABA (gamma-amino butyric acid) receptors belong to the group of pentameric ligand-gated ion channels as serotonin receptors or acetylcholin receptors. Since these membrane proteins have been impossible to chrystallize for a long time and there are still difficulties to determine their structure by X-ray spectometry. However, in recent years it became fashionable to analyze membrane receptors of different types, the determination of the GABA receptor is not a great surprise.

In this week Nature (doi:10.1038/nature13293) Miller and Aricescu from Oxford, UK, show the structure of the so-called β3-homopentamer. BTW that only two authors succeded in this task comes as a surprise.

The GABA receptor is involved in a number of diseases: epilepsy, insomnia, anxiety and panic disorders, has a role in alcohol abuse, binds to benzodiapines. Miller and Aricescu have chrystallized the receptor with a so far unkown agonist (a molecule to activate): benzamidine which allows predictions about the way ligands are bound and how they function.

The paper shows a abundance of beautiful  structural graphs which were drawn with Pymol a nice program used by myself in Hormone und Hormonsystem.

How microRNA work and influence tumour growth

Cell physiology, Genetics, Transformation

The analysis of tumour remains fascinating. While e.g. viruses, methylation of DNA, gene silencing, mutations and deletions have been recognized for some time to play major roles in tumour development, a new player has emerged only recently: microRNA or miRNA. An Open Access review in Current Biology ( http://dx.doi.org/10.1016/j.cub.2014.06.043) features this new class of molecules and describes how they act on tumours. A must read!

Seasonal Regulation of Endocrine Functions.

Biochemistry, Brain, Cell physiology, Endocrinology, Evolution, Hormones,

Almost any animal regulates its metabolism as well as its reproductive life according to the time of the year. (The fact that some domestic animals do not is the exception). This dependence on the season has long been a mystery for endocrinologists. Even then it was found that the Nucleus suprachiasmaticus in the hypothalamus controls and generates a circadian (daily) rhythm which is reflected in all animals analyzed the circannual (yearly) rhythm remained obcur.

Recent developments have shown that some pituitary cells in Pars tuberalis (PT; close to the pituitary stalk) measure the length of day via the melatonin they receive. Since melatonin is only produced in the dark, much melatonin means long nights and few melatonin means short nights. These cells therefore have been named calendar cells.

In an Open Access review in the Journal of Endocrinology Shona Wood and Andrew Loudon have summarized what is known about the physiology and biochemistry of this circannual regulation. They show that thyriod hormones and their conversion from thyroxine to triiodothyronine by deiodinase are an important part in the short day response. They analyse the melatonin response in the PT. They also show how clock genes are differential regulated during the seasons. Finally they show that a ancient gene, the eye absent protein 3 (EYA3) is specifically upregulated when the days get longer.

These genes are ancient and found in insects as well as in birds and mammals pointing to a very old mechanism.

Nice paper, worth studying!

 

Caspases 4, 5 and 11 are Intracellular LPS Receptors

Biochemistry, Cell physiology, Endotoxin, Immunology, Innate defense, , ,

A LPS receptor has already been identified by Beutler and colleagues. This finding was awarded the NOBEL prize in 2011. In the actual issue of Nature (doi:10.1038/nature13683) Shi and colleagues describe the role of caspases – enzymes triggerung cell death called apoptosis – as intracellular receptors for LPS.

When LPS is delived intracellarly into macrophages, epithelial cells or keratinocytes these cells undergo necrosis. The process is specific for intact Lipid A. Murine caspase-11 as well as human caspases 4 and 5 bind to LPS and Lipid A. They induce what is called pyroptosis. The paper is nicely done, however, one might wonder when and how LPS is released from the phagolysosome and becomes available within a cell.

From Dinos to Birds – a problem of size

Cell physiology, Evolution, , ,

In the Science journal there is a remarkable report (DOI: 10.1126/science.1252243) by Lee et al. on the evolution of birds from dinosauri. A lineage is depicted which comprises 12 different independent steps in size reduction. These steps occurred mostly long before the first flying animal hatched. A Perspective article (DOI: 10.1126/science.1257633) by M.J. Benton puts this paper in its context: 20 years ago the evolution of birds was believed to occur within 10 Millions of years. This article summarizes the research done since: Around 50 Millions of year were necessary to the steps to reduce the animal to the size of Archeopteryx and further to that e.g. of a swallow. Some of the intermediate species had feathers, some were “paragliders”, but only Archaeopteryx developed free-flying.

Benton argues that the minaturization was caused by an environmental change i.e. that they tried to live on trees. The gain when living in a tree environment would be safety from predators and a wealth of additional food. Possible.

The authors sampled 120 therapods and early birds. That by itself is a tremendous achievement and makes their analysis fairly sound. Excellent work!