Transcription factors are key cellular components that control gene expression: their activities determine how cells function and respond to the environment. Currently, there is great interest in research into human transcriptional regulation. However, surprisingly little is known about these regulators themselves. For example, how many transcription factors does the human genome contain? How are they expressed in different tissues? Are they evolutionarily conserved? Here, we present an analysis of 1,391 manually curated sequence-specific DNA-binding transcription factors, their functions, genomic organization and evolutionary conservation. Much remains to be explored, but this study provides a solid foundation for future investigations to elucidate regulatory mechanisms underlying diverse mammalian biological processes.

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A census of human transcription factors: function, expression and evolution

Initiation of translation in prokaryotes and eukaryotes.

Glucose-6-phosphate dehydrogenase deficiency

The present invention is directed to secreted and transmembrane polypeptides and to nucleic acid molecules encoding those polypeptides. Also provided herein are vectors and host cells comprising those nucleic acid sequences, chimeric polypeptide molecules comprising the polypeptides of the present invention fused to heterologous polypeptide sequences, antibodies which bind to the polypeptides of the present invention and to methods for producing the polypeptides of the present invention.

Secreted and Transmembrane Polypeptides and Nucleic Acids Encoding the Same

Genetic events in cancer activate signalling pathways that alter cell metabolism. Clinical evidence has linked cell metabolism with cancer outcomes. Together, these observations have raised interest in targeting metabolic enzymes for cancer therapy, but they have also raised concerns that these therapies would have unacceptable effects on normal cells. However, some of the first cancer therapies that were developed target the specific metabolic needs of cancer cells and remain effective agents in the clinic today. Research into how changes in cell metabolism promote tumour growth has accelerated in recent years. This has refocused efforts to target metabolic dependencies of cancer cells as a selective anticancer strategy.

/pdf/targeting-cancer-metabolism-a-therapeutic-window-opens-4eayk4wjss.pdf

Targeting cancer metabolism: a therapeutic window opens

During centriole duplication, a new centriole of defined length forms adjacent to the pre-existing centriole. The centriolar protein CPAP is under tight cell-cycle control and controls centriole length through its intrinsic tubulin-dimer binding activity.

CPAP is a cell-cycle regulated protein that controls centriole length.

Centriole duplication involves the growth of a procentriole next to the parental centriole. Mutations in STIL and CPAP/CENPJ cause primary microcephaly (MCPH). Here, we show that human STIL has an asymmetric localization to the daughter centriole and is required for procentriole formation. STIL levels oscillate during the cell cycle. Interestingly, STIL interacts directly with CPAP and forms a complex with hSAS6. A natural mutation of CPAP (E1235V) that causes MCPH in humans leads to significantly lower binding to STIL. Overexpression of STIL induced the formation of multiple procentrioles around the parental centriole. STIL depletion inhibited normal centriole duplication, Plk4-induced centriole amplification, and CPAP-induced centriole elongation, and resulted in a failure to localize hSAS6 and CPAP to the base of the nascent procentriole. Furthermore, hSAS6 depletion hindered STIL targeting to the procentriole, implying that STIL and hSAS6 are mutually dependent for their centriolar localization. Together, our results indicate that the two MCPH-associated proteins STIL and CPAP interact with each other and are required for procentriole formation, implying a central role of centriole biogenesis in MCPH.

/pdf/the-human-microcephaly-protein-stil-interacts-with-cpap-and-2qy1zrry0n.pdf

The human microcephaly protein STIL interacts with CPAP and is required for procentriole formation

Using a yeast two-hybrid system, we isolated a novel human centrosomal protein, CPAP (centrosomal P4.1-associated protein), which specifically interacts with the head domain of the 135-kDa protein 4.1R isoform (4.1R-135). Sequence analysis revealed that the carboxyl terminus of CPAP has 31.3% amino acid identity with human Tcp-10 (a t-complex responder gene product). Interestingly, most of the sequence identity is restricted to two conserved regions. One carries a leucine zipper, which may form a series of heptad repeats involved in coiled-coil formation; the other contains unusual glycine repeats with unknown function. Immunofluorescence analysis revealed that CPAP and γ-tubulin are localized within the centrosome throughout the cell cycle. CPAP cosediments with γ-tubulin in sucrose gradients and coimmunoprecipitates with γ-tubulin, indicating that CPAP is a part of the γ-tubulin complex. Furthermore, functional analysis revealed that CPAP is localized within the center of microtubule asters and may participate in microtubule nucleation. The formation of microtubule asters was significantly inhibited by anti-CPAP antibody. Together, these observations indicate that CPAP may play an important role in cell division and centrosome function.

Protein 4.1 R-135 Interacts with a Novel Centrosomal Protein (CPAP) Which Is Associated with the γ-Tubulin Complex

Centrioles are cylindrical structures that are usually composed of nine triplets of microtubules (MTs) organized around a cartwheel-shaped structure. Recent studies have proposed a structural model of the SAS-6-based cartwheel, yet we do not know the molecular detail of how the cartwheel participates in centriolar MT assembly. In this study, we demonstrate that the human microcephaly protein, CEP135, directly interacts with hSAS-6 via its carboxyl-terminus and with MTs via its amino-terminus. Unexpectedly, CEP135 also interacts with another microcephaly protein CPAP via its amino terminal domain. Depletion of CEP135 not only perturbed the centriolar localization of CPAP, but also blocked CPAP-induced centriole elongation. Furthermore, CEP135 depletion led to abnormal centriole structures with altered numbers of MT triplets and shorter centrioles. Overexpression of a CEP135 mutant lacking the proper interaction with hSAS-6 had a dominant-negative effect on centriole assembly. We propose that CEP135 may serve as a linker protein that directly connects the central hub protein, hSAS-6, to the outer MTs, and suggest that this interaction stabilizes the proper cartwheel structure for further CPAP-mediated centriole elongation.

/pdf/human-microcephaly-protein-cep135-binds-to-hsas-6-and-cpap-4vhuumnx0f.pdf

Tang K. Tang

Papers

CPAP is a cell-cycle regulated protein that controls centriole length.

The human microcephaly protein STIL interacts with CPAP and is required for procentriole formation

Protein 4.1 R-135 Interacts with a Novel Centrosomal Protein (CPAP) Which Is Associated with the γ-Tubulin Complex

Human microcephaly protein CEP135 binds to hSAS-6 and CPAP, and is required for centriole assembly.

Dynamic localization and functional implications of Aurora-C kinase during male mouse meiosis.