New publication by cancer biology guru Tyler Jacks in June edition of PNAS identifies novel tumor suppressor Snf5. This protein induces Ink4a/Arf in the presents of active Kras oncogene. These findings offer a novel therapy opportunity targeting Ras in cancer.

Kras is one of three Ras family members that promote cell proliferation, differentiation and survival. Kras mutations leading to constitutive activation is major tumor promoting factors. The Ink4a/Arf is a locus coding two proteins p16(Ink4a) and p19(Arf) which are responsible for controlling cell proliferation. In many tumors loss of Ink4a/Arf tumor suppressive functions is necessary for Kras-mediated tumorigenesis. Mechanism underlying the interplay between Ras and the Ink4a/Arf was unknown insofar. The paper by Young and Jacks provide evidence that Snf5 prevents tumorigenesis by Kras by activating Ink4a/Arf suppressive actions. Snf5 is part of the SWI/SNF chromatin remodeling complex and by changing position of nucleosomes enhances expression of Ink4a/Arf in presents of oncogenic Kras.

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Chemical Party – Video

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Will stem cells repair the heart ?

Cardiologists hope new treatment can prolong the lives of patients with dilated cardiomyopathy (DCM). Doctors are investigating whether patients with an irreversible heart condition can prolong their lives by having stem cells taken from their hip and injected into the damaged organ.

Researchers led by cardiologist Professor Anthony Mathur from The Barts Medical School in London are about to start the world’s first randomized control trial exploring whether stem cell therapy can repair the patient’s heart. 90 volunteers will be taken for the trail: half will have stem cells taken from the bone marrow of their hip and injected into their heart, the other half will have their stem cells frozen and be given placebo injections, but will undergo the therapy if the trial is successful.

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August 13. In today’s isse of the Science John Mascola’s lab from National Institute of Allergy and Infectious Diseases published brakethrough resusts, which give a boost for HIV vaccine design.

Human immunodeficiency virus (HIV) is a lentivirus (a member of the retrovirus family) that causes acquired immunodeficiency syndrome (AIDS) a condition in humans in which the immune system begins to fail, leading to life-threatening opportunistic infections. In 1983, two separate research groups led by Robert Gallo and Luc Montagnier independently declared that a novel retrovirus may have been infecting AIDS patients. Since then extensive effort was dedicated to find vaccine against HIV virus.

Dr. Mascola’s group has contributed imersealy to this quest. Their discovered two potent human antibodies that can stop more than 90 percent of known HIV strains from infecting human cells in the laboratory, and have demonstrated how one of these disease-fighting proteins accomplishes this feat. According to the scientists, these antibodies could be used to design improved HIV vaccines, or could be further developed to prevent or treat HIV infection. Additionaly the method used to find these antibodies could be applied to isolate therapeutic antibodies for other infectious diseases as well.

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Xavier Caubit and colleagues from the National Center for Scientific Research (CNRS) in Marseille, France published in July edition of the Journal of Neuroscience that the first breath of mammals draw after birth is controlled by a single gene. So far it was a mystery how newborns take-up air to lungs after long life in a fluid-filled womb and more importantly why this mechanism fatally fails in some individuals i.e. in human diseases such as sudden infant death syndrome and sleep apnoea.

The authors show that mice deficient for the zinc finger protein Teashirt 3 (TSHZ3) fail to breathe and die at birth. Tshz3 mutant embryos have no defects in lung cells but rather in the brain cells that tell the muscles involved in breathing what to do. There are two areas in the brain known to be the key for breathing. The first is a set of cells responsible for controlling muscles that open the airways and move chest muscles. The second is the respiratory rhythm generator (RRG) – a kind of pacemaker that produces an oscillating rhythm in the brainstem and controls autonomous breathing. Tshz3 mutant mice had the RRG neurons present but not properly developed thus animals have no rhythmic activity triggering motoneurons that control muscles of the lung.

It is fascinating that a single gene seems to be essential for a key component of the complex neural networks that regulate breathing. Knowing the genetic basis of breathing will permit development of diagnostic tests and ultimately therapeutic interventions that will help fatal breathing failure of newborns.

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Group of Professor Scott W. Lowe from the CSHL published in the April issue of Cancer Cell the detailed investigation on how Rb regulates many aspects of DNA synthesis when cells enter senescence.

Retinoblastoma (Rb) and Retinoblastoma-like proteins (p107 and p130) belong to the pocket protein family and are transcriptional repressors. Rb is a tumor suppressors that if mutated or inactivated (i.e. by human papillomaviruses E7 protein) can lead to cancer. One of the most difficult conundrums is association between Rb and cellular senescence. Apparently, loss of Rb leads to a decreased senescence whereas loss of p107 or p130 has no effect on this process.

The authors investigated gene loci that are affected when Rb, p107, or p130 are knocked down. They used microarrays and chromatin immunoprecipitation followed by sequencing. The genes targeted by Rb vary substantially depending on the growth condition of the cells (growing vs quiescent vs senescent).

It turns out that genes involved in DNA replication are highly dependent on Rb in senescent cells. Since silencing of Rb, but not p107 or p130, induces cyclin E1, MCM2, MCM3, and origin recognition complex subunit 1 (Orc1) in senescent cells, this might explain why not all pocket proteins are equally suited to regulating senescence.  This excellent study is very extensive and contains lots of information, however it can be plainly summarized: Rb acts in a coordinated fashion to shut down DNA synthesis when cells enter senescence.

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The group of Professor Richard Young from Whitehead Institute-MIT published in the April issue of Cell an important study of a novel mechanism for Myc on the pause release of RNA polymerase II (Pol II) that globally impacts gene expression.

Myc transcription factor is widely known to bind many actively transcribed genes in embryonic stem cells, but how this impacts gene expression has been unclear.

The authors revealed transcriptional pause release as a broad regulator of gene expression in mammalian cells following transcription initiation in a unidirectional or bidirectional manner. Furthermore, in embryonic stem cells Myc releases promoter proximal pausing through the recruitment of the positive transcription elongation factor b (P-TEFb).

This manuscript provides a novel insight into the function of Myc with important mechanistic implications for reprogramming and tumorigenesis.

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Dr. Vousden’s group published in the December 2009 issue of Cell an important paper showing that the activity of mutant p53 controls tumor cell invasion by a p63-dependent induction of integrin and epidermal growth factor receptor (EGFR) trafficking.

Expression of mutant p53 is often observed in human cancers and has been linked to poor outcome, suggesting a prometastatic role in addition to loss of tumor suppressive function. Vousden’s Lab use a powerful experimental approach of in vitro and in vivo tumor models to show that p53 mutations: 175H and 273H that are commonly found in human cancers promote recycling of integrins and epidermal growth factor receptor (EGFR) to the cell surface, thereby increasing the invasiveness of the tumor.

The revealed mechanism suggests that over-expression of mutant p53 in H1299 lung cancer cells (which lack endogenous p53) promotes an interaction between integrin alpha5beta1 and Rab-coupling protein (RCP), a known regulator of integrin and EGFR trafficking. Recycling of the alpha5beta1/EGFR/RCP complex to the cell surface leads to constitutive integrin/EGFR signaling that drives invasion and metastasis. The reverse is observed when endogenous mutant p53 is downregulated using siRNA in cancer cell lines A431 and MDA-MB-231

The authors also provide strong evidence that recycling of integrin/EGFR by mutant p53 is linked to its ability to inhibit transcriptional function of p63, although molecular details of this pathway remain to be determined. It will be interesting to explore the extent to which this regulation extends to other integrins, or integrin-associated cell surface proteins, which have been functionally linked to cancer progression.

This paper is important for our understanding of tumor metastasis and might be crucial for tumor metastasis prevention and therapy.

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Group of Dr. Pelicci (photo) from Italy presented in  the September 2009 issue of Cell an illuminating study that is the first to link p53 tumor suppressor status to the execution of symmetric versus asymmetric divisions of mammary stem cells or ErbB2 tumor-derived mammary cancer stem cells.

The tumor suppressor p53 is a master regulator of cellular homeostasis. P53 protein surveys cellular damage and principally contributes to the decision between quiescence, proliferation, and senescence. Loss-of-function mutations in p53 lead to tumorigenic growth. Interestingly, it is suggested that many types of cancer are described to depend on the self-renewal of cancer stem cells. Pelicci’s lab investigated a clear role of p53 in the regulation of normal and cancer stem cell self-renewal.

The authors used ErbB2 transgenic mice to demonstrate that the ErbB2 (which causes reduction of p53 levels) mammary cancer stem cells have increased symmetric division and replicative potential, and that there is a direct correlation between the ErbB2 gene and the replicative potential of mammary stem cells. The authors also showed that it is p53 that regulates the polarity of cell division in mammary stem cells. Significantly, p53 restoration in vivo reduces the number of cancer stem cells and the size of the tumor. Although the molecular mechanism by which p53 influences cell division polarity remains to be elucidated, this work contribute enormously to our understanding how p53 deregulates cancer stem cell self-renewal and drives tumor growth.

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Ontario Cancer Institute based Dr. Khokha and colleagues report in the June edition of Nature the fascinating study ‘Progesterone induces adult mammary stem cell expansion’ suggesting that a high number of menstrual cycles correlates with increased risk of breast cancer. The authors present evidence that progesterone could act on cell transformation through periodic induction of mammary stem cell expansion.

Reproductive history is the strongest risk factor for breast cancer after age, and genetic predisposition. The authors study mammary stem cells (MaSCs) which are located within a specialized niche in the basal epithelial compartment. MaSCs can be regulated locally and by systemic mechanisms. The model studied in this publication is the mouse oestrus cycle. The authors show that the MaSC pool increases 14-fold during maximal progesterone levels at the luteal dioestrus phase. Progesterone acts on luminal cells, which express steroid receptors elevating Wnt4 and RANKL (receptor activator for nuclear factor kappa B ligand). In turn, basal stem cells show a parallel increase of the receptors for these signals and cyclin D1 expression, which might be responsible for stem cell expansion. Another report in the same Nature issue also implicates RANKL in the response of mammary stem cells to progesterone (by Asselin-Labat et al.)

MaSCs are putative targets for cell transformation events leading to breast cancer and their expansion increase the risk of transformation.

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The important and surprising report was published by Dr. Peter and colleagues in the April issue of Nature. The paper presents a paradoxical finding that CD95 (also called Fas and APO-1), a death receptor that regulates tissue homeostasis mainly in the immune system through the induction of apoptosis, play a role in during cancer progression.

Counterintuitive to its role in apoptosis loss of CD95 reduces tumour growth. The authors found that CD95 activation in an autocrine manner promotes tumor growth and that the tumour promoting activity of CD95 is signaled through the c-Jun N-terminal kinase (JNK) pathway. The authors methodically used many various mouse cancer models (ovarian and hepatocellular carcinoma) and techniques to support their conclusion. This unexpected growth promoting function of CD95 has important implications in cancer therapy.

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June 14, 2010. Barks et al. published fascinating study in the journal ChemBioChem, which helps us understanding how life on Earth emerged. It is one of the greatest scientific challenges and mounting evidence suggests that at early stage of evolution RNA played a more central role, before DNA and protein enzymes appeared. However, scientists attempting to understand how the building blocks of RNA originated on Earth were particularly challenged. While the three bases of RNA – adenine (A), cytosine (C) and uracil (U) – could be created by heating a simple precursor compound in the presence of certain naturally occurring catalysts, guanine (G) the forth building blok of RNA had not been observed as a product of the same reactions. Barks and colleagues show for the first time that guanine (G) can be produced by subjecting a solution of formamide to ultraviolet radiation during heating.

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Dr. Loning Fu and colleagues presents in the June edition of the PlosONE journal (open access journal with first time calculated impact factor of 4.5) intriguing results on circadian homeostasis disruption and tumorigenesis. This landmark paper gives us new insight into the mechanism by which ‘jet lag’ can have potentially tumorigenic effects.

The authors show that many circadian rhythms regulating genes can play important roles in tumorigenesis. Mice lacking the circadian genes Period1 and 2 (Per) or Cryptochrome1 and 2 (Cry) are deficient in cell cycle regulation and Per2 mutant mice are prone to radiation-induced cancer development.

Importantly, similar tumor-promoting effects can be observed in wild-type mice treated with both irradiation and chronic jet lag. Of note, female wt mice were more susceptible to carcinogenic effects of these treatments than males.

The authors suggest that tumor suppression in vivo is a clock-controlled physiological function. The key factor that coordinates the central clock tumor suppression function may be the sympathetic nervous system, best known for the ‘fight or flight’ response. Even a single cycle of jet lag can disrupt the sympathetic nervous system regulation of peripheral clocks and alter regulation of p53 and Myc, genes critical in the development of cancer.

Dr. Loning Fu and her research team show elegantly that frequent disruption of circadian rhythm is an important tumor-promoting factor.

Genentech, Inc based research team of Dr. Johnson published in the June edition of Nature Biotechnology a study that provides a rigorous evaluation of whether genetically engineered mouse models of cancer are suitable for assessing drug responses in the cancer patients in the clinic.

The study investigates mouse models of lung and pancreatic cancer that exhibit tissue specific activation of the Kras oncogene. Mice are treated with drugs that are currently in phase 3 of clinical trails in order to evaluate the mouse model suitability for this kind of study. Two drugs, epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) inhibitors, were tested in these mouse models. Using standard clinical endpoints, including overall survival and progression-free survival, the drug responses seen in the mouse models were similar to those seen in patient studies. Johnson’s team provides promising evidence of potentially high value of genetically modified mouse models of cancer for preclinical studies. However, mouse models are more complex and costly than standard methods of drug evaluation like cell lines mouse tumor xenograft models, with more drugs in the preclinical pipeline, there is clearly a need for improved preclinical models. The next critical step is using mouse models for new therapies and novel drug response prediction.