EDITOR'S PICK: Vitamin D3 provides the skin with protection from harmful microbes
Skin wounds breach the physical barrier that protects the body from harmful microbes in the environment. To counter this breach, wounding triggers an immune response that includes the production of antimicrobial peptides and the upregulation of receptors that recognize microbial components. However, the factors that trigger this immune response have not been well defined.
In a study appearing online on February 8 in advance of publication in the March print issue of the Journal of Clinical Investigation, Richard Gallo and colleagues from the University of California at San Diego now show that wounding to the skin of humans triggers the production (by skin cells known as keratinocytes) of the active form of vitamin D3, and that this induces increased expression of the antimicrobial peptide cathelicidin and the microbial recognition receptors TLR2 and CD14. Further analysis showed that wounding induced keratinocyte expression of the enzyme responsible for converting inactive vitamin D3 to active vitamin D3 (CYP27B1) and that this could be recapitulated in vitro by culturing keratinocytes in the presence of the soluble factor TGF-beta-1. The authors therefore suggest that soluble factors present in wounds, such as TGF-beta-1, induce the expression of CYP27B1, which enables keratinocytes to produce active vitamin D3 that, in turn, induces the upregulation of some components of the immune response and protects us from harmful microbes.
TITLE: Injury enhances TLR2 function and antimicrobial peptide expression through a vitamin D-dependent mechanism
Richard L. Gallo
University of California at San Diego, San Diego, California, USA.
Phone: (858) 552-8585 ext. 6149; Fax: (858) 552-7436; E-mail: email@example.com.
View the PDF of this article at: https://www.the-jci.org/article.php?id=30142
EDITOR'S PICK: Possible genetic link to schizophrenia identified
Several neurological and psychiatric disorders, including schizophrenia, alcoholism, and Parkinson's disease, are associated with changes in the brain that affect the nerves that communicate with each other through the naturally-produced chemical dopamine. One protein that is crucial for dopamine-mediated neuronal communication in animals is DARPP-32. However, very little is known about the function of this protein in humans.
In a study appearing online on February 8 in advance of publication in the March print issue of the Journal of Clinical Investigation, Daniel Weinberger and colleagues from the National Institutes of Health show that the gene that encodes DARPP-32 exhibits genetic variation. One particular variant that increased expression of the mRNA encoding DARPP-32 in the brain was associated with increased performance in a number of cognitive tests, including IQ and memory tests. This variant was also associated with changes in the structure and function of part of the brain known as the neostriatum, as well as changes in the ability of the neostriatum to communicate with the frontal lobe. Importantly, preliminary analysis indicated that this variant was associated with an increased risk of schizophrenia, although further studies will be necessary to confirm this association.
TITLE: Genetic evidence implicating DARPP-32 in human frontostriatal structure, function, and cognition
Daniel R. Weinberger
National Institute for Mental Health, National Institutes of Health, Bethesda, Maryland, USA.
Phone: (301) 402-7564; Fax: (301) 480-7795; E-mail: firstname.lastname@example.org.
View the PDF of this article at: https://www.the-jci.org/article.php?id=30413
MICROBIOLOGY: Efficient consumption of copper allows fungus to infect the brain
Infection with the fungus Cryptococcus neoformans is a problem for individuals whose immune system is compromised (for example individuals with HIV and individuals who are taking chemotherapeutics to treat cancer). It can cause either cryptococcal pneumonia or, more seriously, meningoencephalitis. In a study that appears online on February 8 in advance of publication in the March print issue of the Journal of Clinical Investigation, researchers from the University of Illinois at Chicago show that in mice, the infecting fungus must be adapted to grow in the presence of low levels of copper if it is to efficiently infect the brain and cause meningoencephalitis.
Peter Williamson and colleagues showed that C. neoformans lacking a protein that is essential for it to take up copper from its environment (Cuf1) are impaired in their ability to infect the brain and cause fatal meningoencephalitis. By contrast, these mutant C. neoformans infect the lung as efficiently as C. neoformans expressing Cuf1. Consistent with this, bacteria expressing high levels of a protein controlled by Cuf1 (Ctr4) were found in the brain of mice and humans infected with C. neoformans. This study indicates that one factor that can limit the growth of C. neoformans in the brain of mice and humans is low levels of copper, but that this is not a factor limiting growth in the lung. The authors therefore suggest that determining the level of Ctr4 expressed by the C. neoformans infecting an individual might help determine that individual's risk of developing meningoencephalitis.
TITLE: Role of a CUF1/CTR4 copper regulatory axis in the virulence of Cryptococcus neoformans
Peter R. Williamson
University of Illinois at Chicago, Chicago, Illinois, USA.
Phone: (312) 996-6070; Fax: (312) 413-1657; E-mail: email@example.com.
Sherri McGinnis González
Office of Public Affairs, University of Illinois at Chicago, Chicago, Illinois, USA
Phone: (312) 996-8277; Fax: (312) 413-1883; E-mail: firstname.lastname@example.org
View the PDF of this article at: https://www.the-jci.org/article.php?id=30006
PULMONARY: Don't stop here: why only some cystic fibrosis patients respond to treatments that prevent the generation of truncated proteins
Individuals with the genetic lung disorder cystic fibrosis (CF) lack any functional CFTR protein because their genes that encode this protein carry a mutation. One mutation (the W1282X mutation) that results in CF does so because it causes the cellular machinery that converts the initial product of a gene (mRNA) into a functional protein to prematurely stop making CFTR protein. Agents (such as gentamicin) that enable the protein-generating machinery to ignore such mutations have shown benefit in some, but not all, CF patients with the W1282X mutation. In a study that appears online on February 8 in advance of publication in the March print issue of the Journal of Clinical Investigation, researchers from The Hebrew University of Jerusalem, Israel, describe a potential molecular explanation for the distinct responsiveness of patients with Cf to treatment with gentamicin.
Batsheva Kerem and colleagues found that CF patients with the W1282X mutation who responded to treatment with gentamicin expressed more nonsense CFTR mRNA than patients who did not respond to treatment. Further analysis showed that different cell lines from CF patients with the W1282X mutation had distinct abilities to destroy nonsense mRNA. Inhibiting the destruction of nonsense mRNA in these cell lines increased the amount of nonsense CFTR mRNA present, making them more susceptible to the ability of gentamicin to induce the production of functional CFTR protein. This study suggests that the ability of an individual's affected cells to destroy nonsense mRNA determines how responsive CF patients with the W1282X mutation are likely to be to treatment with gentamicin. Such observations might also extend to other genetic disorders in which mutations causing the cellular machinery to prematurely stop making protein have been identified, such as Duchenne muscular dystrophy.
TITLE: Nonsense-mediated mRNA decay affects nonsense transcript levels and governs response of cystic fibrosis patients to gentamicin
The Hebrew University of Jerusalem, Jerusalem, Israel.
Phone: +972-2-6585689; Fax: +972-2-6584810; E-mail email@example.com.
View the PDF of this article at: https://www.the-jci.org/article.php?id=28523
ONCOLOGY: HMGA1 stops p53 in its tracks in cancer cells
Overexpression of a protein known as HMGA1 has been associated with many types of cancer in humans. Previous studies have shown that HMGA1 decreases the ability of p53 to inhibit cell death by a process known as apoptosis; inhibition of p53-mediated apoptosis causes tumors to develop in both animals and humans. However, precisely how HMGA1 mediates its pro-tumorigenic effects on p53 have not been clearly established. Now, researchers from the Istituto Nazionale dei Tumori Regina Elena, Italy, show that in human cancer cell lines, HMGA1 inhibits p53-mediated apoptosis by interfering with the protein HIPK2, which helps p53 initiate apoptotic cell death.
In the study, which appears online on February 8 in advance of publication in the March print issue of the Journal of Clinical Investigation, Silvia Soddu and colleagues found that overexpression of HMGA1 inhibited p53-mediated apoptosis and caused HIPK2 to relocate from the cell nucleus to the cytoplasm. Further, expression of HIPK2 was required for HMGA1 to inhibit p53-mediated apoptosis. Importantly, analysis of human breast cancer samples indicated that overexpression of HMGA1 correlated with the presence of HIPK2 in the cytoplasm and low levels of apoptotic cells, even in the presence of normal p53. This study therefore identifies a new mechanism by which p53-mediated apoptosis can be inhibited, leading to the development of cancer.
TITLE: High-mobility group A1 inhibits p53 by cytoplasmic relocalization of its proapoptotic activator HIPK2
Istituto Nazionale dei Tumori Regina Elena, Rome, Italy.
Phone: +39-065266-2563; Fax: +39-065266-2505; E-mail: firstname.lastname@example.org.
View the PDF of this article at: https://www.the-jci.org/article.php?id=29852
ONCOLOGY: To be benign or malignant: mTOR makes the decision
Tuberous sclerosis complex (TSC) is a genetic disorder that results in sufferers developing benign tumors in many parts of their body. It is caused by genetic mutation of either of two genes, TSC1 or TSC2. The proteins encoded by these genes are negative regulators of a signaling pathway that is initiated at the cell surface by a ligand binding to PDGFR and that involves activation of PI3K, AKT, and mTOR. The fact that individuals with TSC develop only benign tumors is somewhat surprising because genetic mutations that cause increased PDGFR, PI3K, and AKT activity are associated with malignant cancer, as are inactivating genetic mutations of other negative regulators of this signaling pathways (including PTEN). In a study appearing online on February 8 in advance of publication in the March print issue of the Journal of Clinical Investigation, researchers from the Chinese Academy of Medical Sciences and Peking Union Medical College, People's Republic of China, use mouse models of TSC to provide a potential explanation for the fact that individuals with TSC develop only benign tumors.
The lack of malignant tumors in mice expressing decreased levels of TSC1 or TSC2 is associated with decreased PDGFR expression and decreased PI3K and AKT activity, despite increased mTOR activity. Hongbing Zhang and colleagues now show that in mouse cell lines, activation of PI3K or AKT, as well as inhibition of PTEN, results in decreased PDGFR expression and negative feedback to dampen AKT activity, despite increased mTOR activity. Furthermore, inhibiting mTOR restored PDGFR expression levels and AKT activity in mouse cell lines expressing decreased levels of TSC1 or TSC2, and overexpression of active AKT or PDGFR in such cells rendered them able to induce malignant tumors when transplanted into immunocompromised mice. This study therefore demonstrates that increased mTOR activity decreases PDGFR expression and AKT activity in mouse cells expressing decreased levels of TSC1 or TSC2. More importantly, it offers a potential explanation for the observation that humans expressing mutant forms of TSC1 or TSC2 develop only benign tumors.
TITLE: PDGFRs are critical for PI3/Akt activation and negatively regulated by mTOR
Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People's Republic of China.
Phone: +86-10-6529-6945; Fax: +86-10-6529-6945; E-mail: email@example.com.
View the PDF of this article at: https://www.the-jci.org/article.php?id=28984
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