p57KIP2 is a potent tight-binding inhibitor of several G1 cyclin complexes, and is a negative regulator of cell proliferation. The gene encoding human p57KIP2 is located on chromosome 11p15.5, a region implicated in both sporadic cancers and Beckwith-Wiedemann syndrome (BWS), a cancer syndrome, making it a tumor suppressor candidate. Several types of childhood tumors including Wilms' tumor, adrenocortical carcinoma and rhabdomyosarcoma display a specific loss of maternal 11p15 alleles, suggesting that genomic imprinting plays an important part. Genetic analysis of the familial BWS has indicated maternal carriers and suggested a role in genomic imprinting. Previously, we demonstrated that p57KIP2 is imprinted in the mouse. Here we describe the genomic imprinting of human p57KIP2 and the reduction of its expression in Wilms' tumors. High resolution mapping locates p57KIP2 in the region responsible for both tumor suppressivity and BWS.
To better understand the regulatory mechanisms in gene expression of human cardiomyocytes, we studied the expression of MEF2 genes encoding transcription factors during the course of cardiac development. Expression of all four MEF2 transcripts (MEF2A, MEF2B, MEF2C, and MEF2D) were detected in all developmental stage of the human heart, while Mef2b transcripts were down-regulated in mouse heart development. Although none of the MEF2 genes, besides mouse Mef2b, exhibited any remarkable quantitative change in their transcripts, qualitative changes in MEF2 transcripts were found during the course of cardiac development. In particular, MEF2D transcripts showed prominent changes by alternative splicing in the perinatal period. MEF2D transcripts containing the 21-base exon (exon b) were predominantly expressed after birth. At the same time, transcripts of the alpha myosin heavy chain (alphaMHC) gene increased after birth, as the splicing pattern in transcripts of the cardiac troponin T (cTnT) gene changed to decrease the transcripts of cTnT1 after birth. These changes seemed to be correlated with the alternative splicing changes of MEF2 genes, especially MEF2D. The alternative splicing as well as transcriptional regulation in MEF2 genes might be important for regulating the alphaMHC gene and the maturation of cardiomyocytes.
Marfan syndrome (MFS), an autosomal dominant connective tissue disorder, is caused by mutations in the gene encoding fibrillin 1 (FBN1). The clinical spectrum and severity of MFS disorder varies greatly both between and within families. Since there have been only a few reports on the relationship between FBN1 genotypes and clinical phenotypes in Japanese patients, the FBN1 gene was analyzed in 27 Japanese patients diagnosed with MFS. The nucleotide sequence of the 65 exons of the FBN1 gene was analyzed by PCR and direct sequencing. We have identified six polymorphisms and nine mutations including: four missense mutations (C1652Y, Q2054P, D2127Y, C2221R) in six patients, three nonsense mutations (R215X, S813X, R2220X) in three patients, and two frameshift mutations (2567insT, 7790insT) in three patients. Six of these nine mutations were in the calcium‐binding epidermal growth factor‐like domains all causative mutations detected except for C2221R were novel. It has been reported that the severe phenotypes of infantile MFS correlate with mutations in the mid region of FBN1, however, mutations were not detected in this region in the population analyzed in this study. Our results suggest that the location of the mutation is not the sole determinant of phenotypic severity; rather there is some difference in the genetic basis of MFS between Japanese and Caucasian populations. © 2001 Wiley‐Liss, Inc.
Multiple myeloma (MM) is one of the hematological malignancy that is characterized by proliferation of malignant plasma cells. Recent advance in the treatment of MM using newly developed drugs, prognosis of the MM patients have been significantly improved. For example, immunomodulatory drugs (IMiDs) such as thalidomide, lenalidomide and pomalidomide have been developed for treatment of MM. However, IMiDs have only limited effects against MM patients with high risk chromosomal abnormalities such as t(4;14) and del17p (high-risk MM). In 2010, it was reported that IMiDs directly bind to cereblon (CRBN), a component of ubiquitin ligase 3 complex, and induced teratogenicity as well as anti-tumor effects. We have previously reported that a novel phthalimide derivative, 2-(2,6-diisopropylphenyl)-5-amino-1H-isoindole-1,3-dione (TC11) induced apoptosis against high-risk MM cells in vivo and in vitro, and inhibited differentiation of osteoclasts. We also reported that TC11 directly bound to α-tubulin and nucleophosmin-1 (NPM1), but did not bind to CRBN. However, TC11 was not well dissolved in water with only 0.02 mg/mL solubility. Therefore, TC11 showed poor absorption into blood and limited anti-tumor activity when it was intraperitoneally administered in tumor-bearing mice. To resolve these problems, we synthesized PEG(E)-TC11, in which TC11 is linked to polyethylene glycol through an ester bond, and consequently enhanced water solubility of PEG(E)-TC11 to 88.9 mg/mL. PEG(E)-TC11 revealed as potent growth inhibitory effect on high-risk MM cells as TC11 in vitro. In pharmacokinetic study, PEG-modification of TC11 improved the peak blood concentration (Cmax) from 2.6 to 24.4 μM and extended elimination half-life (t1/2) from 1.4 to 2.2 hr when 186 μM/kg of these compounds were intraperitoneally injected. More importantly, these pharmacokinetic improvement led to more potent growth inhibition of MM cells in vivo than TC11. We also explored mechanisms of anti-myeloma effect of PEG(E)-TC11 and found that PEG(E)-TC11 induced apoptosis via G2/M cell cycle arrest. However, unlike IMiDs family, BIACORE assay revealed that PEG(E)-TC11 didn’t directly bind to CRBN, indicating that growth inhibitory effect of PEG(E)-TC11 against MM cells was independent of binding to CRBN. In conclusion, PEGylation of TC11 significantly increased water solubility, resulted in potentiated anti-myeloma activity in vivo. Furthermore, PEG(E)-TC11 inhibited cell growth via G2/M arrest in a CRBN-independent manner. Thus, PEG(E)-TC11 is considered as a candidate compound for overcoming high-risk MM. Citation Format: Shuji Aida, Daiju Ichikawa, Kazuki Iida, Masashi Hozumi, Misa Nakamura, Ryo Uozaki, Nahoko Hashimoto, Mikio Okayama, Yuko Yonemura, Noriko Tabata, Taketo Yamada, Maiko Matsushita, Takeshi Sugai, Hiroshi Yanagawa, Yutaka Hattori. PEG(E)-TC11, a novel polyethylene glycol-linked phthalimide derivative, inhibited high-risk MM cell growth in vivo and in vitro via cell cycle G2/M arrest in a CRBN-independent manner [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5121. doi:10.1158/1538-7445.AM2017-5121
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