Proteolytic activation of CREB3L1 in treating cancers and tissue fibrosis

CREB3L1 的蛋白水解激活治疗癌症和组织纤维化

基本信息

批准号：
9303422
负责人：
JIN YE
金额：
$ 40.5万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-06 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9303422
关键词：
Adipocytes Adipose tissue Adopted Biological Markers Cell Nucleus Cell Proliferation Ceramides Chemotherapy-Oncologic Procedure Clinical Collagen Cytosol Deposition Disease Doxorubicin Drug Targeting Extracellular Matrix Family Fibrosis Genes Genetic Transcription Grant Health Individual Integral Membrane Protein Malignant Neoplasms Membrane Membrane Proteins Mus N-terminal Non-Insulin-Dependent Diabetes Mellitus Obesity Patients Peptide Signal Sequences Pharmacotherapy Physiological Process Proteins Proteolysis Proteolytic Processing Public Health Reagent Research Role Screening procedure Tertiary Protein Structure Testing Tissues Toxic effect Transforming Growth Factor beta United States base cancer cell chemotherapy improved new therapeutic target novel novel strategies pandemic disease prevent public health relevance response secretory protein transcription factor

项目摘要

DESCRIPTION (provided by applicant): The current project continues to focus on a transcription factor called CREB3L1, which is synthesized as a membrane-bound precursor and activated through a process known as regulated intramembrane proteolysis (RIP). The protein contains a single transmembrane helix, with the N-terminal domain facing the cytosol. During the last grant cycle we have determined that TGF-ß induces cleavage of CREB3L1, allowing the N-terminal domain of the protein to enter nucleus where it activates transcription of genes stimulating assembly of collagen- containing extracellular matrix. Since TGF-ß-induced excess deposition of the collagen- containing matrix leads to tissue fibrosis, inhibiting proteolytic activation of CREB3L1 may be useful in treating fibrotic diseases. This hypothesis will be tested in Aim 1 of the proposal in which we will determine the roles of CREB3L1 in obesity-induced fibrosis of adipose tissue using mice in which CREB3L1 is selectively ablated in adipocytes. Achieving this aim may determine whether proteolytic activation of CREB3L1 could be a novel drug target to treat lipotoxicity by inhibiting fibrosis of adipose tissue. In addition to TGF-ß,we have determined that doxorubicin also stimulates cleavage of CREB3L1, allowing the N-terminal domain of the protein to activate genes that inhibit cell proliferation. We demonstrated that doxorubicin blocked proliferation of cancer cells through activating RIP of CREB3L1. This observation led us to propose Aim 2 in which we will determine whether CREB3L1 expression may serve as a biomarker for doxorubicin- based chemotherapy. Achieving this aim will markedly improve the response rate of doxorubicin by allowing identification of patients who are likely to benefit from the drug treatment. We have further determined that doxorubicin activates CREB3L1 cleavage by inducing synthesis of ceramide. A crucial step for ceramide to activate cleavage of CREB3L1 is to invert the membrane orientation of a transmembrane protein called TM4SF20 by blocking the insertion of its signal peptide into membranes. We designate this novel regulatory mechanism as "alternative translocation". Aim 3 of the project is proposed to delineate the mechanism through which transmembrane and secretory proteins are regulated by alternative translocation. Achieving this aim will demonstrate how membrane proteins can adopt different membrane topologies, and how secretory proteins can function intracellularly under certain physiological conditions. This study should profoundly broaden our views to these proteins.

描述（由申请人证明）：当前的项目继续集中在绑定的前体上，并通过称为常规的膜内蛋白质蛋白质（RIP）进行激活。进入核的核激活基因的转录，含胶原蛋白的基质的CREB3L1的TIC激活可能会在治疗纤维化疾病中有用。在肥胖诱导的脂肪组织中，在脂肪细胞中选择了CREB3L1。刺激CREB3L1的裂解thibit细胞增殖。从药物处理中，我们已经通过诱导CLEB3L1的合成来激活CREB3L1的裂解。由替代易位调节。