Mutations of the VHL tumor suppressor gene occur in patients with VHL disease and in the majority of sporadic clear cell renal carcinomas (VHL(-/-) RCC). Loss of VHL protein function is associated with constitutive expression of mRNAs encoding hypoxia-inducible proteins, such as vascular endothelial growth factor. Overproduction of angiogenic factors might explain why VHL(-/-) RCC tumors are so highly vascularized, but whether this overproduction is sufficient for oncogenesis still remains unknown. In this report, we examined the activity of transforming growth factor-alpha (TGF-alpha), another VHL-regulated growth factor. We show that TGF-alpha mRNA and protein are hypoxia-inducible in VHL(-/-) RCC cells expressing reintroduced VHL. In addition to its overexpression by VHL(-/-) RCC cells, TGF-alpha can also act as a specific growth-stimulatory factor for VHL(-/-) RCC cells expressing reintroduced wild-type VHL, as well as primary renal proximal tubule epithelial cells, the likely site of origin of RCC. This role is in contrast to those of other growth factors overexpressed by VHL(-/-) RCC cells, such as vascular endothelial growth factor and TGF-beta1, which do not stimulate RCC cell proliferation. A TGF-alpha-specific antisense oligodeoxynucleotide blocked TGF-alpha production in VHL(-/-) RCC cells, which led to the dependence of those cells on exogenous growth factors to sustain growth in culture. Growth of VHL(-/-) RCC cells was also significantly reduced by a drug that specifically inhibits the epidermal growth factor receptor, the receptor through which TGF-alpha stimulates proliferation. These results suggest that the generation of a TGF-alpha autocrine loop as a consequence of VHL inactivation in renal proximal tubule epithelial cells may provide the uncontrolled growth stimulus necessary for the initiation of tumorigenesis.

Most cell physiology events are dictated by the integration of perceived signals and the elaboration by cells of adapted answers via the execution of proper transcriptional programs. In order to ensure an optimal control of these answers, many regulation mechanisms have been selected throughout the evolution, thus allowing to fine-tune transcript expression. The transcriptional pause and its release by P-TEFb (Positive Transcription Elongation Factor) have been evidenced two decades ago. Since then, the importance of such mechanisms has been highlighted by the association between alterations of this machinery and the appearance of diseases. P-TEFb and Brd4 have thus recently emerged as potential therapeutical targets for cancers and AIDS notably. In this review, we present a brief case history and an up-to-date synthesis of models for transcriptional pause release. We later discuss on the pathophysiological processes associated with this mechanism and clinical trials targeting Brd4 and P-TEFb.

A B 100µV 1 sec F7-T3 T3-T5 T5-O1 Fp1-F3 F3-C3 C3-P3 P3-O1 Fz-Cz Cz-Pz Resp+ Resp-Figure 1. (A) A 15-second-long EEG trace showing right posterior periodic discharges with time-locked tapping (black arrow) on a piezoelectric accelerometer. (B) Axial T1 gadolinium and FLAIR MRI showing occipital meningioma. MULTIMEDIA TEACHING MATERIALTo better serve its mission as the educational journal of the International League Against Epilepsy, Epileptic Disorders created on its website (www.epilepticdisorders.com) a MULTIMEDIA teaching section.In this section, epileptologists are invited to contribute to the multimedia libraries of: short educational videos on specific aspects of semiology of epileptic seizures and electro-clinical features of epilepsy syndromes; structural and/or functional neuroimaging and neuropathology images related to epilepsy; EEG and MEG figures; and videos or images of neurosurgical techniques.The structure of the multimedia submissions should be conceived for educational purposes. Alongside the multimedia material, authors are requested to submit a title and a short abstract (not more than 100 words) summarising the main message, as well as the subtitles of the video sequences or images included and the corresponding key words. Submissions are made via the submission platform: mc.manuscriptcentral.com/epilepticdisorders, under the manuscript type Multimedia Teaching Material, and are peer reviewed. All Multimedia Teaching Material will be constantly and freely accessible on our website.