MicroRNAs (miRs) are non-coding RNAs that inhibit expression of their targets in a sequence-specific manner and play crucial roles during oncogenesis. Here we show that miR-7 inhibits p21-activated kinase 1 (Pak1) expression, a widely upregulated signaling kinase in multiple human cancers including breast and gliomas, by targeting the 3′-UTR of Pak1 mRNA. We noticed an inverse correlation between the levels of endogenous miR-7 and Pak1 expression in human cancer cells. We discovered that endogenous miR-7 expression is positively regulated by a homeodomain transcription factor HoxD10, loss of which leads to an increased invasiveness. The HoxD10 directly interacts with the miR-7 chromatin. Accordingly, the levels of Pak1 protein are progressively upregulated while that of miR-7 and its upstream activator HoxD10 are progressively downregulated in a cellular model of breast cancer progression from low to highly invasive phenotypes. Furthermore, HoxD10 expression in highly invasive breast cancer cells resulted in an increased expression of miR-7 but a reduced Pak1 3′UTR-luciferase activity as well as reduced Pak1 protein. Finally, we show that miR-7 introduction inhibits the motility, invasiveness, anchorage-independent growth and tumorigenic potential of highly invasive breast cancer cells. Collectively, these findings establish for the first time that Pak1 is a target of miR-7 and that HoxD10 play a regulatory role in modifying the expression of miR-7, and consequently, functions of miR7 - Pak1 pathway in human cancer cells.
The p21-activated kinase (PAK) family of serine/threonine kinases plays a pivotal role in physiological processes including motility, survival, mitosis, transcription and translation. PAKs are evolutionally conserved and widely expressed in a variety of tissues and are often over expressed in multiple cancer types. Depending on structural and functional similarities, the six members of PAK family are divided into two groups with three members in each group. Group I PAKs are activated by extracellular signals through GTPase-dependent and independent mechanisms. In contrast, group II PAKs are constitutively active. Over the years, accumulating data from tissue culture models and human tumors has increased our understanding about the biology of PAK family members. In this review, we have summarized the complex regulation of PAK and its downstream diverse myriads of effectors which in-turn are responsible for the biologic effects of PAK family of kinases in cancer cells.
The process of epithelial-mesenchymal transition plays a pivotal role in the conversion of early stage tumors into invasive malignancies,
Our data support a role for Pak1, particular Pak1 localized to the nucleus, in ERalpha signaling and in tamoxifen resistance.
Estrogen receptor ␣ (ER␣) functions as both a transcription factor and a mediator of rapid estrogen signaling. Recent studies have shown a role for ER␣-interacting membranous and cytosolic proteins in ER␣ action, but our understanding of the role of the microtubule network in the modulation of ER␣ signaling remains unclear. Here we found that endogenous ER␣ associates with microtubules through the microtubule-binding protein hematopoietic PBX-interaction protein (HPIP). Biochemical and RNA-interference studies demonstrated that HPIP influences ER␣-dependent rapid estrogen signaling by acting as a scaffold protein and recruits Src kinase and the p85 subunit of phosphatidylinositol 3-kinase to a complex with ER␣, which in turn stimulates AKT and MAPK. We also found that ER␣ interacts with -tubulin through HPIP. Destabilization of microtubules activated ER␣ signaling, whereas stabilization of microtubules repressed ER␣ transcriptional activity in a HPIP-dependent manner. These findings revealed a role for HPIPmicrotubule complex in regulating 17-estradiol-ER␣ responses in mammalian cells and discovered an inherent role of microtubules in the action of nuclear receptor.17-estradiol ͉ estrogen receptor ͉ hematopoietic PBX-interaction protein E strogen regulates a plethora of functionally divergent physiological processes including development, homeostasis, and reproduction (1). The diversity of estrogen action results in part from the ability of estrogen receptors (ERs) to act both as transcription factors that regulate gene expression (i.e., genomic effects) and as signaling proteins that rapidly recruit and activate kinase-dependent signaling pathways (rapid effects). There is growing evidence that a subpopulation of the conventional nuclear steroid receptor localized in the vicinity of the cell membrane mediates many of the rapid signaling actions of steroid hormones; however, membrane receptors unrelated to conventional steroid receptors have also been implicated (2, 3). Several studies support the concept that estrogen can activate multiple cytosolic signaling pathways through direct interactions of conventional estrogen receptor (ER␣ or ER) with various cytoplasmic and membranous proteins, including kinases and adaptor proteins, by forming different multiprotein complexes (2, 4). In addition, sequestration of ER by MTA1s (metastasisassociated antigen 1 short form) also triggers estrogen rapid signaling. So it appears that relative subcellular distribution of ERs plays a critical role in estrogen signaling. Besides these mechanistic studies, recent reports have suggested that extranuclear estrogen signaling is directly implicated in cell migration through actin cytoskeleton remodeling (5).Microtubules are structural components of the cytoskeleton required for cell motility that regulate a variety of signaling pathways, including the inducible nitric oxide synthase, NF-B, ERK, JNK, Wnt, and Hedgehog signaling pathways (6). The functional role of microtubules in signal transduction has been further elucidated ...
Here, we investigated the role of P21-activated kinase 1 (Pak1) signaling in the function of estrogen receptor-A (ER-A) as assessed by serine 305 (S305) activation and transactivation activity of ER. We found that Pak1 overexpression interfered with the antiestrogenic action of tamoxifen upon the ER transactivation function in hormone-sensitive cells. In addition, tamoxifen stimulation led to up-regulation of ER target genes in breast cancer cells with increased Pak1 expression. Tamoxifen also increased Pak1-ER interaction in tamoxifenresistant but not in tamoxifen-sensitive cells. Results from the mutational studies discovered a role of ER-S305 phosphorylation in triggering a subsequent phosphorylation of serine 118 (S118), and these effects were further potentiated by tamoxifen treatment. We found that S305 activation-linked ER transactivation function requires a functional S118, and active Pak1 signaling is required for a sustaining S118 phosphorylation of the endogenous ER. All of these events were positively influenced by tamoxifen and thus may contribute toward the loss of antiestrogenic effect of tamoxifen. These findings suggest that Pak1 signaling-dependent activation of ER-S305 leads to an enhanced S118 phosphorylation presumably due to a conformational change, and such structural modifications may participate in the development of tamoxifen resistance.
Here we define a function of metastasis-associated protein 1 (MTA1), a presumed corepressor of estrogen receptor α (ERα), as a transcriptional activator of Breast Cancer Amplified Sequence 3 (BCAS3), a gene amplified and overexpressed in breast cancers. We identified BCAS3 as a MTA1 chromatin target in a functional genomic screen. MTA1 stimulation of BCAS3 transcription required ERα and involved a functional ERE half-site in BCAS3 . Furthermore, we discovered that MTA1 is acetylated on lysine 626, and that this acetylation is necessary for a productive transcriptional recruitment of RNA polymerase II complex to the BCAS3 enhancer sequence. BCAS3 expression was elevated in mammary tumors from MTA1 transgenic mice and 60% of the human breast tumors, and correlated with the coexpression of MTA1 as well as with tumor grade and proliferation of primary breast tumor samples. These findings reveal a previously unrecognized function of MTA1 in stimulating BCAS3 expression and suggest an important role for MTA1-BCAS3 pathway in promoting cancerous phenotypes in breast tumor cells.
Transcription, splicing, and translation are potentially coordinately regulatable in a temporospatial-dependent manner, although supporting experimental evidence for this notion is scarce. Yeast two-hybrid screening of a mammary gland cDNA library with human p21-activated kinase 1 (Pak1) as bait identified polyC-RNAbinding protein 1 (PCBP1), which controls translation from mRNAs containing the DICE (differentiation control element). Mitogenic stimulation of human cells phosphorylated PCBP1 on threonines 60 and 127 in a Pak1-sensitive manner. Pak1-dependent phosphorylation of PCBP1 released its binding and translational inhibition from a DICE-minigene. Overexpression of PCBP1 also inhibited the translation of the endogenous L1 cell adhesion molecule mRNA, which contains two DICE motifs in the 3 untranslated region. We also found that Pak1 activation led to an increased nuclear retention of PCBP1, recruitment to the eukaryotic translation initiation factor 4E (eIF4E) promoter, and stimulation of eIF4E expression in a Pak1-sensitive manner. Moreover, mitogenic stimulation promoted Pak1-and PCBP1-dependent alternative splicing and exon inclusion from a CD44 minigene. The alternative splicing functions of PCBP1 were in turn mediated by its intrinsic interaction with Caper ␣, a U2 snRNP auxiliary factor-related protein previously implicated in RNA splicing. These findings establish the principle that a single coregulator can function as a signal-dependent and coordinated regulator of transcription, splicing, and translation. differentiation control element ͉ eukaryotic translation initiation factor 4E ͉ p21-activated kinase 1
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