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Cyclin D1 and vitamin D signaling in oral keratinocyte pathophysiology

口腔角质形成细胞病理生理学中的细胞周期蛋白 D1 和维生素 D 信号传导

基本信息

批准号：
8743203
负责人：
SANJAY M MALLYA
金额：
$ 11.55万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-26 至 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8743203
关键词：
Address Androgen Receptor Binding Biochemical Pathway Biological Models Body part CDK4 gene Cancer Survivor Cell Cycle Cell Cycle Progression Cell Cycle Regulation Cell Differentiation process Cell Proliferation Chemicals Chemopreventive Agent Chronic Cyclin D1 Cyclin-Dependent Kinases Data Defect Dermal Development Diet Disease Dysplasia Epithelial Cells Epithelium Esophagus Esthetics Estrogen Receptors Event Functional disorder Gene Expression Gene Targeting Genes Goals Human Intraepithelial Neoplasia Knowledge Lesion Malignant - descriptor Malignant Neoplasms Mediating Mediator of activation protein Medical Modeling Molecular Molecular Genetics Morbidity - disease rate Mus Neoplasms Neoplastic Processes Nuclear Hormone Receptors Nutritional Nutritional status Oncogenes Oncogenic Operative Surgical Procedures Oral Oral cavity Oropharyngeal Squamous Cell Carcinoma Pathway interactions Phenotype Phosphorylation Phosphotransferases Physiology Play Premalignant Process Promoter Regions Public Health Quality of life RXR Radiation therapy Regulation Retinoblastoma Protein Risk Role S Phase STAT3 gene Signal Pathway Signal Transduction Site Supplementation Survival Rate Testing Therapeutic Tongue Transcriptional Regulation Transgenic Mice United States Vitamin D Vitamin D Deficiency Vitamin D3 Receptor Vitamins cancer risk cancer type immunoregulation improved keratinocyte keratinocyte differentiation malignant mouth neoplasm malignant oropharynx neoplasm mortality mouse model neoplastic novel oral carcinogenesis oral dysplasia oral premalignancy overexpression pharynx squamous cell carcinoma public health relevance receptor function transcription factor tumor tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): The focus of this proposal is on the role of the cyclin D1 oncogene in oral cancer. Oropharyngeal squamous cell carcinomas (OSCC) are aggressive tumors that result in significant mortality and morbidity. Frequently, these tumors initiate as a precancerous lesion that develops to an invasive neoplasm. However, the molecular mechanisms underlying the transition to invasive neoplasia are not fully understood. Furthermore, the role of dietary agents in modifying this process has not been studied. The cyclin D1 oncogene plays an important role in OSCC development. Cyclin D1 is a key regulator of the G1-S phase of the cell cycle. Acting via its kinase partners CDK4 and CDK6, it results in phosphorylation of the retinoblastoma protein to effect cell cycle progression. The current paradigm assumes that this is the major mechanism of cyclin D1's oncogenic actions. However, there is emerging evidence that cyclin D1 participates in transcriptional control. We recently discovered that cyclin D1 binds to the vitamin D receptor (VDR) and modulates vitamin D signaling. This finding is particularly significant in that vitamin D plays an essential role in regulation of keratinocyte proliferation and differentiation. The studies described in this proposa will study the intersection between the cyclin D1 and vitamin D signaling pathways. The short-term goals of this proposal are to (1) examine the mechanism by which cyclin D1 deregulates vitamin D signaling and (2) examine role of dietary vitamin D deficiency in modulating the development of oral pre-cancer and cancer. The long-term goal is to study the contribution of vitamin D signaling in oral keratinocyte physiology and pathophysiology, its intersection with oncogenic pathways and its implications for oral carcinogenesis. To achieve these goals two Specific Aims are proposed. Specific Aim 1 will investigate the mechanism by which cyclin D1 deregulates VDR-mediated transcriptional control. Specific Aim 2 will examine the role of dietary vitamin D deficiency in modulating cyclin D1-driven oral pre-cancer using a transgenic mouse model system. These studies will significantly increase our understanding of cyclin D1's oncogenic mechanisms and vitamin D's role in modulating oral cancer risk. Given the emerging problem of vitamin D nutritional status both in the United States as well as globally, our studies have tremendous implications for potential dietary and chemopreventive approaches to oral cancer management. Furthermore, cyclin D1 is an established oncogene for several tumor types and there is growing evidence for vitamin D's role in several cancers. Thus, our studies have potentially broad implications for several other tumors types.

描述（由申请人提供）：本提案的重点是细胞周期蛋白D1癌基因在口腔癌中的作用。口咽部鳞状细胞癌（OSCC）是一种侵袭性肿瘤，导致显著的死亡率和发病率。通常，这些肿瘤起始于癌前病变，发展为侵袭性肿瘤。然而，向侵袭性肿瘤转变的分子机制还不完全清楚。此外，还没有研究过饮食制剂在改变这一过程中的作用。cyclin D1癌基因在口腔鳞癌的发生发展中起重要作用。细胞周期蛋白D1是细胞周期G1-S期的关键调节因子。通过其激酶伴侣CDK 4和CDK 6起作用，导致视网膜母细胞瘤蛋白磷酸化以影响细胞周期进程。目前的范式假设这是细胞周期蛋白D1的致癌作用的主要机制。然而，有新的证据表明，细胞周期蛋白D1参与转录控制。我们最近发现，细胞周期蛋白D1结合维生素D受体（VDR）和调节维生素D信号。这一发现特别重要，因为维生素D在调节角质形成细胞增殖和分化中起重要作用。本提案中描述的研究将研究细胞周期蛋白D1和维生素D信号通路之间的交叉。该提案的短期目标是（1）检查细胞周期蛋白D1失调维生素D信号传导的机制和（2）检查饮食维生素D缺乏在调节口腔癌前病变和癌症发展中的作用。长期目标是研究维生素D信号在口腔角质形成细胞生理学和病理生理学中的作用，其与致癌途径的交叉及其对口腔癌发生的影响。为了实现这些目标，提出了两个具体目标。具体目标1将调查的机制，细胞周期蛋白D1失调VDR介导的转录控制。具体目标2将检查饮食中的维生素D缺乏的作用，在调制细胞周期蛋白D1驱动的口腔癌前病变使用转基因小鼠模型系统。这些研究将显著增加我们对细胞周期蛋白D1的致癌机制和维生素D在调节口腔癌风险中的作用的理解。鉴于美国和全球维生素D营养状况的新问题，我们的研究对口腔癌管理的潜在饮食和化学预防方法具有巨大的影响。此外，细胞周期蛋白D1是几种肿瘤类型的既定致癌基因，越来越多的证据表明维生素D在几种癌症中的作用。因此，我们的研究对其他几种肿瘤类型具有潜在的广泛意义。