Disruption of a GATA4/Ankrd1 signaling axis in cardiomyocytes leads to sarcomere disarray: implications for anthracycline cardiomyopathy.

Doxorubicin (Adriamycin) is an effective anti-cancer drug, but its clinical usage is limited by a dose-dependent cardiotoxicity characterized by widespread sarcomere disarray and loss of myofilaments. Cardiac ankyrin repeat protein (CARP, ANKRD1) is a transcriptional regulatory protein that is extremely susceptible to doxorubicin; however, the mechanism(s) of doxorubicin-induced CARP depletion and its specific role in cardiomyocytes have not been completely defined. We report that doxorubicin treatment in cardiomyocytes resulted in inhibition of CARP transcription, depletion of CARP protein levels, inhibition of myofilament gene transcription, and marked sarcomere disarray.

Transcription of the C. elegans let-7 microRNA is temporally regulated by one of its targets, hbl-1.

The let-7 family of microRNAs (miRNAs) are important regulators of developmental timing and cell differentiation and are often misexpressed in human cancer. In C. elegans, let-7 controls cell fate transitions from larval stage 4 (L4) to adulthood by post-transcriptionally down-regulating lineage-abnormal 41 (lin-41) and hunchback-like 1 (hbl-1).

The let-7 family of microRNAs.

The first two known microRNAs (miRNAs), lin-4 and let-7, were originally discovered in the nematode Caenorhabditis elegans and control the timing of stem-cell division and differentiation. let-7 was subsequently found as the first known human miRNA. let-7 and its family members are highly conserved across species in sequence and function, and misregulation of let-7 leads to a less differentiated cellular state and the development of cell-based diseases such as cancer.

MicroRNAs as potential agents to alter resistance to cytotoxic anticancer therapy.

Tumor cells use preexisting prosurvival signaling pathways to evade the damaging and cytotoxic effects of anticancer agents. Radiation therapy is a primary form of cytotoxic anticancer treatment, but agents that successfully modify the radiation response in vivo are lacking. MicroRNAs (miRNA) are global gene regulators that play critical roles in oncogenesis and have been found to regulate prosurvival pathways.

Micromanagement: a role for microRNAs in mRNA stability.

Small, inhibitory RNA molecules called microRNAs cause large decreases in target protein levels through a post-transcriptional mechanism. Until recently, it was believed this mechanism operated almost exclusively at a step in translation. However, new work has revealed that microRNAs have a second, post-transcriptional mechanism that accelerates the rate of deadenylation, the initial step of mRNA decay.