The CRM1 Nuclear Export Receptor Controls Pathological Cardiac Gene Expression

Abstract

Diverse pathological insults trigger a cardiac remodeling process during which myocytes undergo hypertrophy, with consequent decline in cardiac function and eventual heart failure. Multiple transcriptional regulators of pathological cardiac hypertrophy are controlled at the level of subcellular distribution. For example, prohypertrophic transcription factors belonging to the nuclear factor of activated T cells (NFAT) and GATA families are subject to CRM1-dependent nuclear export but are rapidly relocalized to the nucleus in response to cues for hypertrophic growth. Here, we demonstrate that the antihypertrophic chromatin-modifying enzyme histone deacetylase 5 (HDAC5) is shuttled out of the cardiomyocyte nucleus via a CRM1-mediated pathway in response to diverse signals for hypertrophy. CRM1 antagonists block the agonist-mediated nuclear export of HDAC 5 and repress pathological gene expression and associated hypertrophy of cultured cardiomyocytes. Conversely, CRM1 activity is dispensable for nonpathological cardiac gene activation mediated by thyroid hormone and insulin-like growth factor 1, agonists that fail to trigger the nuclear export of HDAC5. These results suggest a selective role for CRM1 in derepression of pathological cardiac genes via its neutralizing effects on antihypertrophic factors such as HDAC5. Pharmacological approaches targeting CRM1-dependent nuclear export in heart muscle may have salutary effects on cardiac function by suppressing maladaptive changes in gene expression evoked by stress signals.A common mechanism controlling gene expression involves altering the subcellular distribution of transcriptional regulators. A multitude of transcription factors and cofactors possess nuclear localization sequences (NLSs) and nuclear export signals (NESs) that mediate entry into and exit from the nucleus, respectively. Frequently, signal transduction pathways that impinge on transcriptional regulators function by positively or negatively affecting the activities of these intrinsic targeting domains.For proteins over ϳ40 kDa, passage into and out of the nucleus is governed by the nuclear pore complex (NPC), a multisubunit structure embedded in the nuclear envelope (27). Positively charged NLSs are bound by importins ␣ and ␤, which tether cargo to the cytosolic face of the NPC and facilitate translocation of proteins into the nucleus. The CRM1 protein, also referred to as exportin, mediates the transit of proteins out of the nucleus (16), although CRM1-independent mechanisms for nuclear export exist (25, 33). CRM1 binds hydrophobic NESs together with the small GTP binding protein Ran, and these ternary complexes are shuttled out of the nucleus through a series of interactions with the NPC.

Expression of the nuclear export protein chromosomal region maintenance/exportin 1/Xpo1 is a prognostic factor in human ovarian cancer

“…Because strong toxic side effects have been encountered with LMB during clinical trials for cancer, many efforts have focused on novel CRM1 antagonists; and some agents, such as PKF050-638 or 5219668, recently have been identified. 10 The results of the current study demonstrated that CRM1 expression is associated with advanced ovarian carcinomas that have an aggressive behavior. Thus, CRM1 expression is related to poor patient outcome.…”

“…This transporter has a comparably broad substrate range and mediates the export of leucine-rich NES-bearing proteins and the transfer of messenger RNAs (mRNAs). [4][5][6][7][8] Mechanistic studies have demonstrated an increasing number of NEScontaining signaling molecules that depend on the CRM1 nuclear export pathway, p53, 9 histone deacetylase 5 (HDAC5), 10 protein kinase 1 (Akt1), 11 epidermal growth factor receptor (EGFR), 12 and others. 13,14 Therefore, this shuttling process controls several elements of pathways that have been identified as important in tumor biology.…”

Class IIa histone deacetylases: regulating the regulators

“…The nuclear export of class IIa HDACs is inhibited by leptomycin B, which suggests that the export receptor CRM1 may interact with the leucine-rich NES found in class IIa HDACs Harrison et al, 2004). Whereas no CRM1 class IIa HDACs association has ever been formally documented, overexpression of CRM1 promotes cytoplasmic accumulation of HDAC7 .…”

Toward transcriptional therapies for the failing heart: chemical screens to modulate genes

“…Instead, these HDACs are shuttled from the nucleus to the cytoplasm in response to stress (Figure 3), which provides a posttranslational mechanism to override HDACmediated repression of cardiac growth (27,28,31). This redistribution of HDACs frees MEF2 (and other transcription factors) to associate with HATs (32,33), resulting in increased local histone acetylation and activation of downstream genes that promote cell growth.…”