Orphan nuclear receptor NR2E3 is a new molecular vulnerability in solid tumors by activating p53.

The orphan nuclear receptor NR2E3 has emerged as a potential tumor suppressor, yet its precise mechanisms in tumorigenesis require further investigation. Here, we demonstrate that the full-length protein isoform of NR2E3 instead of its short isoform activates wild-type p53 and is capable of rescuing certain p53 mutations in various cancer cell lines. Importantly, we observe a higher frequency of NR2E3 mutations in three solid tumors compared to the reference population, highlighting its potential significance in tumorigenesis.

Identification of Novel Binding Partners for Transcription Factor Emx2.

The mammalian homolog of Drosophila empty spiracles 2 (Emx2) is a homeobox transcription factor that plays central roles in early development of the inner ear, pelvic and shoulder girdles, cerebral cortex, and urogenital organs. The role for Emx2 is best understood within the context of the development of the neocortical region of the cortex, where Emx2 is expressed in a high posterior-medial to low anterior-lateral gradient that regulates the partitioning of the neocortex into different functional fields that perform discrete computational tasks. Despite several lines of evidence demonstrating an Emx2 concentration-dependent mechanism for establishing functional areas within the developing neocortex, little is known about how Emx2 physically carries out this role.

Heterochromatin protein 1 expression is reduced in human thyroid malignancy.

Owing to the loss of heterochromatin integrity that occurs during thyroid tumorigenesis, the expression of Heterochromatin Protein 1 isoforms HP1α and HP1β was assessed by immunohistochemistry in 189 thyroid tumors and non-neoplastic tissues. Expression of HP1β was significantly decreased in all thyroid lesions, except in follicular adenomas, when compared with matched adjacent normal tissue. This loss of HP1β expression may in part be caused by microRNA dysregulation.

Antiapoptotic protein Lifeguard is required for survival and maintenance of Purkinje and granular cells.

Lifeguard (LFG) is an inhibitor of Fas-mediated cell death and is highly expressed in the cerebellum. We investigated the biological role of LFG in the cerebellum in vivo, using mice with reduced LFG expression generated by shRNA lentiviral transgenesis (shLFG mice) as well as LFG null mice. We found that LFG plays a role in cerebellar development by affecting cerebellar size, internal granular layer (IGL) thickness, and Purkinje cell (PC) development.

Lhx2 specifies regional fate in Emx1 lineage of telencephalic progenitors generating cerebral cortex.

Cerebral cortex is comprised of regions, including six-layer neocortex and three-layer olfactory cortex, generated by telencephalic progenitors of an Emx1 lineage. The mechanism specifying region-specific subpopulations in this lineage is unknown. We found that the LIM homeodomain transcription factor Lhx2 in mice, expressed in graded levels by progenitors, determines their regional identity and fate decisions to generate neocortex or olfactory cortex.

Interactions of 40LoVe within the ribonucleoprotein complex that forms on the localization element of Xenopus Vg1 mRNA.

Proline rich RNA-binding protein (Prrp), which associates with mRNAs that employ the late pathway for localization in Xenopus oocytes, was used as bait in a yeast two-hybrid screen of an expression library. Several independent clones were recovered that correspond to a paralog of 40LoVe, a factor required for proper localization of Vg1 mRNA to the vegetal cortex. 40LoVe is present in at least three alternatively spliced isoforms; however, only one, corresponding to the variant identified in the two-hybrid screen, can be crosslinked to Vg1 mRNA.

PAX5 is expressed in small-cell lung cancer and positively regulates c-Met transcription.

PAX5 is a nuclear transcription factor required for B cell development, and its expression was evaluated in upper aerodigestive malignancies and pancreatic cancer by immunoblotting. The PAX5 protein expression was relatively strong in small-cell lung cancer (SCLC, 11/12); however, its expression was not detected in non-SCLC (NSCLC, n=13), mesothelioma (n=7), pancreatic (n=6), esophageal (n=6) and head and neck cancer cell lines (n=12). In comparison, PAX8 and PAX3 expressions were absent or non-detectable in SCLC cell lines; however, PAX8 was expressed in most of the tested NSCLC cell lines (13/13) and also frequently in all the other cell lines.

CREB3L2-PPARgamma fusion mutation identifies a thyroid signaling pathway regulated by intramembrane proteolysis.

The discovery of gene fusion mutations, particularly in leukemia, has consistently identified new cancer pathways and led to molecular diagnostic assays and molecular-targeted chemotherapies for cancer patients. Here, we report our discovery of a novel CREB3L2-PPARgamma fusion mutation in thyroid carcinoma with t(3;7)(p25;q34), showing that a family of somatic PPARgamma fusion mutations exist in thyroid cancer. The CREB3L2-PPARgamma fusion encodes a CREB3L2-PPARgamma fusion protein that is composed of the transactivation domain of CREB3L2 and all functional domains of PPARgamma1.

Peroxisome proliferator-activated receptor-delta induces cell proliferation by a cyclin E1-dependent mechanism and is up-regulated in thyroid tumors.

Peroxisome proliferator-activated receptors (PPARs) are lipid-sensing nuclear receptors that have been implicated in multiple physiologic processes including cancer. Here, we determine that PPARdelta induces cell proliferation through a novel cyclin E1-dependent mechanism and is up-regulated in many human thyroid tumors. The expression of PPARdelta was induced coordinately with proliferation in primary human thyroid cells by the activation of serum, thyroid-stimulating hormone/cyclic AMP, or epidermal growth factor/mitogen-activated protein kinase mitogenic signaling pathways.

Molecular detection of PPAR gamma rearrangements and thyroid carcinoma in preoperative fine-needle aspiration biopsies.

The pathologic diagnosis of thyroid follicular tumors is difficult, particularly in preoperative fine-needle aspiration biopsies. To investigate whether the molecular diagnosis of PPAR gamma rearrangements can detect thyroid carcinomas in fine-needle aspiration biopsies, we performed interphase fluorescence in situ hybridization on 24 thyroid fine-needle aspiration and 17 follow-up thyroidectomy specimens. Two of the 24 fine-needle aspiration biopsies contained PPAR gamma rearrangements, and both were diagnosed suggestive of a thyroid follicular neoplasm by cytology.

Cortical area size dictates performance at modality-specific behaviors.

The mammalian neocortex is organized into unique areas that serve functions such as sensory perception and modality-specific behaviors. The sizes of primary cortical areas vary across species, and also within a species, raising the question of whether area size dictates behavioral performance. We show that adult mice genetically engineered to overexpress the transcription factor EMX2 in embryonic cortical progenitor cells, resulting in reductions in sizes of somatosensory and motor areas, exhibit significant deficiencies at tactile and motor behaviors.

Molecular events in follicular thyroid tumors.

Knowledge of the molecular events that govern human thyroid tumorigenesis has grown considerably in the past ten years. Key genetic alterations and new oncogenic pathways have been identified. Molecular genetic aberrations in thyroid carcinomas bear noteworthy resemblance to those in acute myelogenous leukemias.

Ventralized dorsal telencephalic progenitors in Pax6 mutant mice generate GABA interneurons of a lateral ganglionic eminence fate.

The transcription factor Pax6 is expressed by progenitors in the ventricular zone (VZ) of dorsal telencephalon (dTel), which generate all cortical glutamatergic neurons, but not by progenitors in the medial ganglionic eminence (MGE), which generate cortical GABAergic interneurons (GABA INs), or the lateral ganglionic eminence (LGE), which generate GABA INs that normally migrate to the olfactory bulb. We show that perinatally, Pax6(sey/sey) mice, which lack functional Pax6 protein, have large subpial ectopias in dTel and ventral telencephalon connected by cell streams arising from an aberrant paraventricular ectopia found throughout dTel. The subpial and paraventricular ectopias and connecting cell streams are comprised of postmitotic neurons expressing markers for GABA INs characteristic of a LGE fate.

PIKE-A is amplified in human cancers and prevents apoptosis by up-regulating Akt.

PIKE-A (PIKE-activating Akt), an isoform of PIKE GTPase that enhances phosphatidylinositol 3-kinase (PI3-kinase) activity, specifically binds to active Akt but not PI3-kinase. PIKE-A stimulates Akt activity in a GTP-dependent manner and promotes invasiveness of cancer cell lines. Here, we show that PIKE-A is amplified in a variety of human cancers and that amplified PIKE-A directly stimulates Akt and inhibits apoptosis compared to cells with normal PIKE-A copy number.

The PAX8/PPARgamma fusion oncoprotein transforms immortalized human thyrocytes through a mechanism probably involving wild-type PPARgamma inhibition.

Follicular thyroid carcinoma (FTC) frequently harbors the PAX8/PPARgamma fusion gene (PPFP); however, its oncogenic role and mechanism(s) of action remain undefined. We investigated PPFP's effects on cell growth, apoptosis, cell-cell, and cell-matrix interactions in immortalized human thyroid cells (Nthy-ori 3-1) and NIH 3T3 cells. PPFP expression increased the growth of transient and stable Nthy-ori transfectants ( approximately threefold by 72 h).

PIKE (phosphatidylinositol 3-kinase enhancer)-A GTPase stimulates Akt activity and mediates cellular invasion.

Akt/PKB is a crucial regulator of diverse cellular processes and contributes to cancer progression. Activation of Akt is essentially dependent on phosphatidylinositol (PI) 3-kinase signaling. Here, we describe a novel mediator of Akt that is independent of PI 3-kinase.

RAS point mutations and PAX8-PPAR gamma rearrangement in thyroid tumors: evidence for distinct molecular pathways in thyroid follicular carcinoma.

A series of 88 conventional follicular and Hürthle cell thyroid tumors were analyzed for RAS mutations and PAX8-PPAR gamma rearrangements using molecular methods and for galectin-3 and HBME-1 expression by immunohistochemistry. A novel LightCycler technology-based method was developed to detect point mutations in codons 12/13 and 61 of the H-RAS, K-RAS, and N-RAS genes. Forty-nine percent of conventional follicular carcinomas had RAS mutations, 36% had PAX8-PPAR gamma rearrangement, and only one (3%) had both.

Genetic and biological subgroups of low-stage follicular thyroid cancer.

Investigations of cancer-specific gene rearrangements have increased our understanding of human neoplasia and led to the use of the rearrangements in pathological diagnosis of blood cell and connective tissue malignancies. Here, we have investigated 3p25 rearrangements of the peroxisome proliferator-activated receptor gamma (PPAR gamma) gene in follicular epithelial tumors of the human thyroid gland. Eleven of 42 (26%) low-stage follicular carcinomas, 0 of 40 follicular adenomas, 1 of 30 Hurthle cell carcinomas, 1 of 90 papillary carcinomas, and 0 of 10 nodular goiters had 3p25 rearrangements by interphase fluorescence in situ hybridization.

A homolog of FBP2/KSRP binds to localized mRNAs in Xenopus oocytes.

A Xenopus oocyte expression library was screened for proteins that bind to the 340-nucleotide localization element of Vg1 mRNA. Four different isolates encoded a Xenopus homolog of the human transcription factor, FUSE-binding protein 2 (FBP2). This protein has been independently identified as the splicing regulatory factor KSRP.

Inhibitory effects of peroxisome poliferator-activated receptor gamma on thyroid carcinoma cell growth.

Peroxisome proliferator-activated receptor gamma (PPAR gamma) is a nuclear receptor involved in such cellular processes as adipogenesis, inflammation, atherosclerosis, cell cycle control, apoptosis, and carcinogenesis. PPAR gamma gene mutations have been found in 4 of 55 sporadic colon cancers, and a chimeric PAX8-PPAR gamma 1 gene frequently generates a chromosomal translocation in thyroid follicular carcinomas, implicating PPAR gamma in tumor suppression. We investigated whether PPAR gamma is involved in the growth regulation of normal and tumor thyroid cells.

PAX8-PPARgamma rearrangement in thyroid tumors: RT-PCR and immunohistochemical analyses.

A PAX8-PPARgamma rearrangement has been recently identified in follicular thyroid carcinomas, but not in follicular adenomas or other thyroid tumors. We report here the analyses of PAX8-PPARgamma in a series of 118 thyroid tumors using a newly developed RT-PCR assay to detect this rearrangement in frozen and paraffin-embedded tissues and using immunostaining with a PPARgamma antibody. PAX8-PPARgamma was detected by RT-PCR in eight of 15 (53%) follicular carcinomas and two of 25 (8%) follicular adenomas but not in 35 papillary carcinomas (including 12 follicular variants), 12 Hurthle cell carcinomas, 12 Hurthle cell adenomas, two anaplastic carcinomas, one poorly differentiated carcinoma, or 16 hyperplastic nodules.