Hypertrophic growth is a risk factor for mortality in heart diseases. Mechanisms are lacking for this global increase in RNA and protein per cell, which underlies hypertrophy. Hypertrophic signals cause phosphorylation of the RNA polymerase II C-terminal domain, required for transcript elongation. RNA polymerase II kinases include cyclin-dependent kinases-7 (Cdk7) and Cdk9, components of two basal transcription factors. We report activation of Cdk7 and -9 in hypertrophy triggered by signaling proteins (Galphaq, calcineurin) or chronic mechanical stress. Only Cdk9 was activated by acute load or, in culture, by endothelin. A preferential role for Cdk9 was shown in RNA polymerase II phosphorylation and growth induced by endothelin, using pharmacological and dominant-negative inhibitors. All four hypertrophic signals dissociated 7SK small nuclear RNA, an endogenous inhibitor, from cyclin T-Cdk9. Cdk9 was limiting for cardiac growth, shown by suppressing its inhibitor (7SK) in culture and preventing downregulation of its activator (cyclin T1) in mouse myocardium.Note: In the AOP version of this article, the numbering of the author affiliations was incorrect. This has now been fixed, and the affiliations appear correctly online and in print.

Cathelicidins are a family of myeloid antimicrobial peptide precursors that have been identified in several mammalian species (Zanetti, M., Gennaro, R., and Romeo, D. (1995) FEBS Lett. 374, 1-5). Two novel bovine congeners have been deduced from cDNA. Their C-terminal sequences of 27 and 28 residues correspond to putative antimicrobial peptides with a cationic N-terminal region predicted to assume an amphipathic ␣-helical conformation followed by a hydrophobic C-terminal tail. Peptides corresponding to these sequences have been chemically synthesized and shown to exert a potent antimicrobial activity against Gram-negative and Grampositive bacteria, including methicillin-resistant Staphylococcus aureus, and fungi. Both peptides are also cytotoxic to human erythrocytes and neutrophils, although at higher than microbicidal concentrations. The target selectivity has been improved by synthesizing truncated analogues, comprising only the 18 N-terminal residues, which show a great reduction in cytotoxic, but not in antimicrobial activity. The involvement of the C-terminal hydrophobic tail in the cytotoxic activity has been further demonstrated by inducing a major loss of activity in an analogue after replacing highly hydrophobic residues with more hydrophilic ones.Research on naturally occurring antimicrobial peptides has resulted in the recognition of a surprisingly large number of peptides that are produced by animals and plants so as to fight infections (1, 2). In recent years, an additional impulse to the identification of novel antimicrobial peptides has come from the demand for new drugs ensuing from the emergence of multidrug resistant pathogens (3). Accordingly, the conversion of naturally occurring antimicrobial peptides into drugs is a goal that is currently being pursued by several research groups and biotechnology companies.We and others have recently described a number of novel mammalian antimicrobial peptides that are derived from a group of precursors named cathelicidins (4). Precursors of this family are stored in the neutrophil granules of various mammalian species. They show a highly conserved N-terminal prosequence and a markedly varied C-terminal domain that exhibits antimicrobial activity after the propiece has been removed. Cathelicidin-derived antimicrobial peptides range in length from 12 to about 100 residues, and include ␣-helical peptides, e.g. human LL-37/hCAP18 (5-7) and pig PMAP-37 (8); linear peptides with one or two predominant amino acids, e.g. the bovine Pro-and Arg-rich Bac5 and Bac7 (9) and the Trp-rich indolicidin (10); and peptides with one or two disulfide bonds, e.g. bovine cyclic dodecapeptide (11) and pig protegrins (12).A characteristic feature of cathelicidins is the extensive conservation of their mRNAs in the 5Ј region corresponding to the 5Ј noncoding region, the signal peptide and the prosequence. This feature has allowed identification of the mRNAs of several novel congeners in various mammalian species. At present, more than 20 cathelicidins with molecular masses of 16 ...

Myogenic transcription is repressed in myoblasts by serum-activated cyclin-dependent kinases, such as cdk2 and cdk4. Serum withdrawal promotes muscle-speci®c gene expression at least in part by down-regulating the activity of these cdks. Unlike the other cdks, cdk9 is not serum-or cell cycle-regulated and is instead involved in the regulation of transcriptional elongation by phosphorylating the carboxyl-terminal domain (CTD) of RNA polymerase II. While ectopic expression of cdk2 together with its regulatory subunits (cyclins E and A) inhibits myogenic transcription, overproduction of cdk9 and its associated cyclin (cyclin T2a) strengthens MyoD-dependent transcription and stimulates myogenic di erentiation in both MyoD-converted ®broblasts and C2C12 muscle cells. Conversely, inhibition of cdk9 activity by a dominant negative form (cdk9-dn) represses the myogenic program. Cdk9, cyclinT2 and MyoD can be detected in a multimeric complex in C2C12 cells, with the minimal cdk9-binding region of MyoD mapping within 101 ± 161 aa of the bHLH region. Finally, cdk9 can phosphorylate MyoD in vitro, suggesting the possibility that cdk9/cycT2a regulation of muscle di erentiation includes the direct enzymatic activity of the kinase on MyoD.