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Human Mena (hMENA), an actin regulatory protein of the ENA/VASP family, cooperates with ErbB receptor family signaling in breast cancer. It is overexpressed in high-risk preneoplastic lesions and in primary breast tumors where it correlates with HER2 overexpression and an activated status of AKT and MAPK. The concomitant overexpression of hMENA and HER2 in breast cancer patients is indicative of a worse prognosis. hMENA is expressed along with alternatively expressed isoforms, hMENA11aand hMENAΔv6 with opposite functions. A novel role for the epithelial-associated hMENA11aisoform in sustaining HER3 activation and pro-survival pathways in HER2-overexpressing breast cancer cells has been identified by reverse phase protein array and validated in vivo in a series of breast cancer tissues. As HER3 activation is crucial in mechanisms of cell resistance to PI3K inhibitors, we explored whether hMENA11ais involved in these resistance mechanisms. The specific hMENA11adepletion switched off the HER3-related pathway activated by PI3K inhibitors and impaired the nuclear accumulation of HER3 transcription factor FOXO3a induced by PI3K inhibitors, whereas PI3K inhibitors activated hMENA11aphosphorylation and affected its localization. At the functional level, we found that hMENA11asustains cell proliferation and survival in response to PI3K inhibitor treatment, whereas hMENA11asilencing increases molecules involved in cancer cell apoptosis. As shown in three-dimensional cultures, hMENA11acontributes to resistance to PI3K inhibition because its depletion drastically reduced cell viability upon treatment with PI3K inhibitor BEZ235. Altogether, these results indicate that hMENA11ain HER2-overexpressing breast cancer cells sustains HER3/AKT axis activation and contributes to HER3-mediated resistance mechanisms to PI3K inhibitors. Thus, hMENA11aexpression can be proposed as a marker of HER3 activation and resistance to PI3K inhibition therapies, to select patients who may benefit fr

Cervical artery dissection (CeAD), a mural hematoma in a carotid or vertebral artery, is a major cause of ischemic stroke in young adults although relatively uncommon in the general population (incidence of 2.6/100,000 per year)1. Minor cervical traumas, infection, migraine and hypertension are putative risk factors1-3, and inverse associations with obesity and hypercholesterolemia are described3,4. No confirmed genetic susceptibility factors have been identified using candidate gene approaches5. We performed genome-wide association studies (GWAS) in 1,393 CeAD cases and 14,416 controls. The rs9349379[G] allele (PHACTR1) was associated with lower CeAD risk (odds ratio (OR) = 0.75, 95% confidence interval (CI) = 0.69-0.82; P = 4.46 × 10-10), with confirmation in independent follow-up samples (659 CeAD cases and 2,648 controls; P = 3.91 × 10-3; combined P = 1.00 × 10-11). The rs9349379[G] allele was previously shown to be associated with lower risk of migraine and increased risk of myocardial infarction6-9. Deciphering the mechanisms underlying this pleiotropy might provide important information on the.

A large complex of proteins, called CENPs, are associated with centromeric DNA. Some of them exhibit a cell cycle-related expression (e.g., CENP-E and -F) and are required for the transition from interphase to mitosis, whereas constitutive proteins (e.g., CENP-A, -B, -C, -G, and -H) reside permanently at the centromere and are essential for the correct kinetochore assembly. Poly(ADP-ribose) polymerase-1 (PARP-1), which plays an active role in many basic processes, was described as a possible regulator of CENPs. By multicolor immunofluorescence we therefore analyzed the distribution of PARP-1 and its interaction with CENP-B, -E, and -F during mitosis and apoptosis. © 2009 New York Academy of Sciences.

We present a method to investigate the kinetics of protein folding and the dynamics underlying the formation of secondary and tertiary structures during the entire reaction. By writing the solution of the Fokker-Planck equation in terms of a path integral, we derive a Hamilton-Jacobi variational principle from which we are able to compute the most probable pathway of folding. The method is applied to the folding of the Villin headpiece subdomain simulated using a Go model. An initial collapsing phase driven by the initial configuration is followed by a rearrangement phase, in which secondary structures are formed and all computed paths display strong similarities. This completely general method does not require the prior knowledge of any reaction coordinate and is an efficient tool to perform simulations of the entire folding process with available computers.

Angiotensin II (Ang II) action on vascular smooth muscle cells is not limited to contraction, but includes long term effects such as hypertrophy and hyperplasia. This implies a complex pattern of gene modulation, which remains largely unknown. We used the mRNA differential display method to screen rat aortic smooth muscle cells cultured with or without Ang II. We demonstrated that Ang II induces the expression of calponin, a 34-kD protein, which has been shown to regulate smooth muscle cell contraction and to be a marker of smooth muscle cell differentiation. We demonstrated this induction both at gene and protein level in vascular smooth muscle cells. Calponin mRNA was dose-dependently induced by Ang II, with an effect still evident at 5 x 10(-9)M, and it did not require active protein synthesis, since cycloheximide treatment did not suppress this induction. Calponin gene expression was maximal at 3 h, while protein expression was maximal at 8 h. Calponin expression was completely abolished by the AT1 receptor antagonist, losartan, at 1 x 10(-6)M. Our data demonstrate that Ang II increases calponin gene expression and protein level in rat aortic smooth muscle cells in vitro.