A novel mechanism of cell growth regulation by Cell Cycle and Apoptosis Regulatory Protein (CARP)-1

Here we investigated whether CARP-1 is involved in signaling induced by the protein kinase A inhibitor H89. Treatments of human breast cancer cells with H89 resulted in apoptosis that involved enhanced CARP-1 threonine phosphorylation and expression. Depletion of CARP-1, on the other hand, abrogates apoptosis induced by H89. CARP-1 binds with signal transducer TAZ and over-expression of TAZ inhibits apoptosis by CARP-1. CARP-1 (651-759) interacts with a novel, N-terminal epitope of TAZ. H89 treatment stimulates threonine phosphorylation of CARP-1 (651-759), while substitution of threonine667 to alanine interferes with its binding with TAZ and apoptosis by H89. In addition, expression of wild type or CARP-1 (651-759) causes loss of c-myc expression due, in part, to suppression of c-myc transcription.CARP-1 threonine667 regulates H89-dependent signaling by a novel pathway that involves modulation of CARP-1 interaction with TAZ and transcriptional down-regulation of c-myc.Apoptosis is essential in maintaining tissue homeostasis in a host of conditions including development, wound healing, and elimination of infectious pathogens. Defective apoptosis is often encountered in many diseases including cancer [1,2]. Although, anticancer therapeutics function in part by targeting apoptosis pathways, development of drug resistance remains a problem and therefore warrants identification and exploitation of additional apoptosis transducers to effectively manage drug-resistant cancers. CARP-1/CCAR1 is a perinuclear protein that functions in regulating signaling by growth factors as well as chemotherapeutics such as adriamycin, etoposide, and iressa [3,4]. CARP-1 is a phospho-protein that is a target of phosphorylation by the DNA-damage induced ATM kinase [5], and serves as a key co-activator of the steroid/thyroid receptor family of transcription factors as well as tumor suppressor p53 [6]. Although ectopic expression of CARP-1 diminishes levels of cell-cycle regulatory proteins s