Promiscuous and lineage-specific roles of cell cycle regulators in haematopoiesis

Haematopoietic cell number is maintained by a delicate balance between cell proliferation, differentiation and death. Gene knockout studies in mice have revealed the complex roles of cyclins, CDKs, and CDK inhibitors in regulating cell proliferation and differentiation in the haematopoietic system. These studies point to families of cell cycle regulators which display both redundant and unique roles within a lineage and developmental-stage specific manner. Moreover, the promiscuity of these cell cycle regulators is critical for haematopoietic cell proliferation and differentiation. In this review, we discuss the current evidence from mouse models that the complexity and multifarious nature of the haematopoietic system is critical for its form and function

SUMOylation inhibits FOXM1 activity and delays mitotic transition

The forkhead box transcription factor FOXM1 is an essential effector of G2/M-phase transition, mitosis and the DNA damage response. As such, it is frequently deregulated during tumorigenesis. Here we report that FOXM1 is dynamically modified by SUMO1 but not by SUMO2/3 at multiple sites. We show that FOXM1 SUMOylation is enhanced in MCF-7 breast cancer cells in response to treatment with epirubicin and mitotic inhibitors. Mutation of five consensus conjugation motifs yielded a SUMOylation-deficient mutant FOXM1. Conversely, fusion of the E2 ligase Ubc9 to FOXM1 generated an auto-SUMOylating mutant (FOXM1-Ubc9). Analysis of wild-type FOXM1 and mutants revealed that SUMOylation inhibits FOXM1 activity, promotes translocation to the cytoplasm and enhances APC/Cdh1-mediated ubiquitination and degradation. Further, expression of the SUMOylation-deficient mutant enhanced cell proliferation compared with wild-type FOXM1, whereas the FOXM1-Ubc9 fusion protein resulted in persistent cyclin B1 expression and slowed the time from mitotic entry to exit. In summary, our findings suggest that SUMOylation attenuates FOXM1 activity and causes mitotic delay in cytotoxic drug response

Nonquantum Gravity

One of the great challenges for 21st century physics is to quantize gravity and generate a theory that will unify gravity with the other three fundamental forces of nature. This paper takes the (heretical) point of view that gravity may be an inherently classical, i.e., nonquantum, phenomenon and investigates the experimental consequences of such a model. At present there is no experimental evidence of the quantum nature of gravity and the liklihood of definitive tests in the future is not at all certain. If gravity is, indeed, a nonquantum phenomenon, then it is suggested that evidence will most likely appear at mesoscopic scales.Comment: essentially the same as the version that appears in Foundations of Physics, 39, 331 (2009

Cold Collision Frequency Shift of the 1S-2S Transition in Hydrogen

We have observed the cold collision frequency shift of the 1S-2S transition in trapped spin-polarized atomic hydrogen. We find $\Delta \nu_{1S-2S} = -3.8(8)\times 10^{-10} n Hz cm^3$, where $n$ is the sample density. From this we derive the 1S-2S s-wave triplet scattering length, $a_{1S-2S}=-1.4(3)$ nm, which is in fair agreement with a recent calculation. The shift provides a valuable probe of the distribution of densities in a trapped sample.Comment: Accepted for publication in PRL, 9 pages, 4 PostScript figures, ReVTeX. Updated connection of our measurement to theoretical wor

Airborne rhinovirus detection and effect of ultraviolet irradiation on detection by a semi-nested RT-PCR assay

BACKGROUND: Rhinovirus, the most common cause of upper respiratory tract infections, has been implicated in asthma exacerbations and possibly asthma deaths. Although the method of transmission of rhinoviruses is disputed, several studies have demonstrated that aerosol transmission is a likely method of transmission among adults. As a first step in studies of possible airborne rhinovirus transmission, we developed methods to detect aerosolized rhinovirus by extending existing technology for detecting infectious agents in nasal specimens. METHODS: We aerosolized rhinovirus in a small aerosol chamber. Experiments were conducted with decreasing concentrations of rhinovirus. To determine the effect of UV irradiation on detection of rhinoviral aerosols, we also conducted experiments in which we exposed aerosols to a UV dose of 684 mJ/m(2). Aerosols were collected on Teflon filters and rhinovirus recovered in Qiagen AVL buffer using the Qiagen QIAamp Viral RNA Kit (Qiagen Corp., Valencia, California) followed by semi-nested RT-PCR and detection by gel electrophoresis. RESULTS: We obtained positive results from filter samples that had collected at least 1.3 TCID(50 )of aerosolized rhinovirus. Ultraviolet irradiation of airborne virus at doses much greater than those used in upper-room UV germicidal irradiation applications did not inhibit subsequent detection with the RT-PCR assay. CONCLUSION: The air sampling and extraction methodology developed in this study should be applicable to the detection of rhinovirus and other airborne viruses in the indoor air of offices and schools. This method, however, cannot distinguish UV inactivated virus from infectious viral particles

Sense and sensitivity : FOXO and ROS in cancer development and treatment

Forkhead box O (FOXO) transcription factors are at the center of an emerging paradigm that links longevity, cell fate, and tumor development. Key to these processes is the ability of FOXO to regulate, and be regulated by, oxidative stress. Perturbation of the mechanisms that tightly couple reactive oxygen species (ROS) production, oxidative stress signaling, and FOXO activity to the subsequent cellular response is a pivotal step in cancer development and progression. Consequently, the ROS-FOXO pathway is a major therapeutic target in cancer, not only as it mediates the cellular response to chemotherapy, but also because it underpins drug resistance. As the intimate and reciprocal relation between FOXO and ROS is being unravelled, new opportunities arise to develop more-effective cancer treatments that circumvent resistance to the conventional cytotoxic drugs. Antioxid. Redox Signal. 14, 675—687

Definition of microRNAs that repress expression of the tumor suppressor gene FOXO1 in endometrial cancer

Endometrial cancer is the most common malignancy of the lower female reproductive tract. The tumor suppressor FOXO1 is downregulated in endometrial cancer compared with normal endometrium but the underlying mechanisms are not well understood. Using microRNA (miR) target prediction algorithms, we identified several miRs that potentially bind the 3′-untranslated region of FOXO1 transcripts. Expression profiling of normal and malignant endometrial samples by quantitative real-time PCR and Northern blot analysis revealed an inverse correlation between the levels of FOXO1 protein and the abundance of several of the in silico–predicted miRs, suggesting that loss of FOXO1 expression in endometrial cancer may be mediated by miRs. To determine the role of candidate miRs, we used the endometrial cancer cell lines HEC-1B and Ishikawa, which express FOXO1 at high and low levels, respectively. Expression of miR-9, miR-27, miR-96, miR-153, miR-182, miR-183, or miR-186, but not miR-29a, miR-128, miR-152, or miR-486 mimetics in HEC-1B cells was sufficient to significantly reduce the abundance of FOXO1. Conversely, FOXO1 expression was efficiently restored in the Ishikawa cell line upon simultaneous inhibition of miR-9, miR-27, miR-96, miR-153, miR-183, and miR-186. Moreover, induction of FOXO1 in Ishikawa cells by miR inhibitors was accompanied by G1 cell cycle arrest and cell death, and was attenuated by the small interfering RNA–mediated downregulation of FOXO1 expression. Our findings identify several miRs overexpressed in endometrial cancer that function in concert to repress FOXO1 expression. Further, aberrant miR expression results in deregulated cell cycle control and impaired apoptotic responses, and thus, may be central to endometrial tumorigenesis. Cancer Res; 70(1); 367–7