Proteasome-mediated Degradation of Hematopoietic Progenitor Kinase 1 in Pancreati

蛋白酶体介导的胰腺造血祖细胞激酶 1 的降解

• 批准号: 8220828
• 负责人: Huamin Wang
• 金额: $ 17.18万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8220828
• 关键词: Apoptosis; CUL1 gene; Cell Cycle Arrest; Cell Line; Cell Proliferation; Cells; Complex; Data; Development; Growth; Hematopoietic; Human; In Vitro; MAPK8 gene; Malignant - descriptor; Malignant Epithelial Cell; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediating; Messenger RNA; Molecular; Molecular Target; Names; Neoplasm Metastasis; Oncogene Proteins; Oncogenic; Pancreatic Ductal Carcinoma; Pancreatic Intraepithelial Neoplasia; Pancreatic duct; Pathway interactions; Play; Protein-Serine-Threonine Kinases; Proteins; Regulation; Role; Sampling; Serine; System; Threonine; Time; Tumor Suppressor Proteins; Ubiquitination; Up-Regulation; Xenograft Model; cancer therapy; hematopoietic progenitor kinase 1; in vivo; insight; multicatalytic endopeptidase complex; neoplastic cell; novel; novel therapeutics; overexpression; protein degradation; protein expression; public health relevance; small hairpin RNA; tumor growth; tumorigenesis; ubiquitin-protein ligase

DESCRIPTION (provided by applicant): HPK1, also named MAP4K1, is a mammalian Ste20-related serine/threonine kinase and has been shown to inhibit Erk and activate NF?B and JNK pathways (1). While a number of studies have identified the role of HPK1 in proliferation, differentiation and apoptosis in hematopoietic cells, the role of HPK1 in malignant transformation, proliferation, and invasion in malignancies has not been examined. Recently, we demonstrated that HPK1 protein is expressed in normal pancreatic ducts, but is lost in >95% of pancreatic ductal carcinoma (PDC) samples. The loss of HPK1 protein is strongly associated with the progression from low-grade pancreatic intraepithelial neoplasia (PanIN) to invasive PDC. More importantly, restoring wild type HPK1 protein expression in PDC cells resulted in cell cycle arrest and growth inhibition, which is due in part to up- regulation of p21 and p27 (2). Thus, our data showed, for the first time, that HPK1 may function as a novel tumor suppressor and its loss plays a critical role in the development of PDC. In addition, we have also demonstrated that loss of HPK1 in PDC is due to proteasome-mediated protein degradation, but not at the mRNA levels and that HPK1 kinase activity is required for the loss of HPK1 protein in PDC (2). Little is known about the regulation of HPK1 in vivo. Recently, we have identified Fbw8 as the E3 ligase that is responsible for proteasome-mediated degradation of HPK1 protein in PDC. In this proposal, we will examine the novel molecular mechanisms by which Fbw8 targets HPK1 protein for degradation and the oncogenic functions of Fbw8 in pancreatic cancer. Accomplishment of the proposed studies will not only reveal the novel molecular pathways of HPK1 regulation in pancreatic cancer, but also identify new targets for pancreatic cancer treatment. We have the following two Specific Aims: Specific Aim 1: To examine the mechanism of ubiquitin E3 ligase, Fbw8, in proteasome-mediated degradation of HPK1 protein in pancreatic cancer. Specific Aim 2: To examine the function of Fbw8-mediated HPK1 degradation in tumor growth and metastasis of pancreatic cancer. PUBLIC HEALTH RELEVANCE: Proteasome-mediated Degradation of Hematopoietic Progenitor Kinase 1 in Pancreatic Cancer We recently demonstrated that HPK1 function as a novel tumor suppressor and that proteasome-mediated degradation of HPK1 protein is strongly associated with the progression from low-grade pancreatic intraepithelial neoplasia (PanIN) to invasive pancreatic cancer. In this proposal, we will examine the detailed molecular mechanisms of proteasome-mediated degradation of HPK1 protein and to examine the possible oncogenic functions of the newly identified ubiquitin-E3 ligase, Fbw8, that is responsible for HPK1 degradation in pancreatic cancer. Accomplishment of the proposed studies will reveal novel pathways of HPK1 regulation in pancreatic cancer and identify novel targets for pancreatic cancer treatment.

描述（由申请人提供）：HPK 1，也称为MAP 4K 1，是哺乳动物Ste 20相关的丝氨酸/苏氨酸激酶，并已显示抑制Erk和激活NF？B和JNK通路（1）。虽然许多研究已经确定了HPK 1在造血细胞的增殖、分化和凋亡中的作用，但尚未研究HPK 1在恶性肿瘤的恶性转化、增殖和侵袭中的作用。最近，我们证实HPK 1蛋白在正常胰腺导管中表达，但在>95%的胰腺导管癌（PDC）样品中丢失。HPK 1蛋白的缺失与从低度胰腺上皮内瘤变（PanIN）到侵袭性PDC的进展密切相关。更重要的是，在PDC细胞中恢复野生型HPK 1蛋白表达导致细胞周期停滞和生长抑制，这部分是由于p21和p27的上调（2）。因此，我们的数据首次表明，HPK 1可能作为一种新的肿瘤抑制因子发挥作用，其缺失在PDC的发展中起着关键作用。此外，我们还证明了PDC中HPK 1的丢失是由于蛋白酶体介导的蛋白降解，但不是在mRNA水平上，并且PDC中HPK 1蛋白的丢失需要HPK 1激酶活性（2）。HPK 1在体内的调控机制还知之甚少。最近，我们已经确定Fbw 8作为E3连接酶，负责蛋白酶体介导的HPK 1蛋白在PDC中的降解。在这个提议中，我们将研究Fbw 8靶向HPK 1蛋白降解的新分子机制以及Fbw 8在胰腺癌中的致癌功能。这些研究的完成不仅将揭示胰腺癌中HPK 1调控的新分子途径，而且将为胰腺癌的治疗找到新的靶点。具体目的1：研究泛素E3连接酶Fbw 8在胰腺癌中蛋白酶体介导的HPK 1蛋白降解中的作用机制。具体目的2：研究Fbw 8介导的HPK 1降解在胰腺癌生长和转移中的作用。 公共卫生关系：蛋白酶体介导的造血祖细胞激酶1在胰腺癌中的降解我们最近证明HPK 1作为一种新的肿瘤抑制因子发挥作用，并且蛋白酶体介导的HPK 1蛋白降解与从低度胰腺上皮内瘤变（PanIN）到侵袭性胰腺癌的进展密切相关。在这个提议中，我们将研究蛋白酶体介导的HPK 1蛋白降解的详细分子机制，并研究新鉴定的泛素-E3连接酶Fbw 8的可能致癌功能，Fbw 8负责胰腺癌中HPK 1的降解。这些研究的完成将揭示胰腺癌中HPK 1调控的新途径，并确定胰腺癌治疗的新靶点。

项目成果

Perineural and intraneural invasion in posttherapy pancreaticoduodenectomy specimens predicts poor prognosis in patients with pancreatic ductal adenocarcinoma.

• DOI: 10.1097/pas.0b013e31824104c5
• 发表时间: 2012-03
• 期刊: The American journal of surgical pathology
• 作者: Chatterjee D;Katz MH;Rashid A;Wang H;Iuga AC;Varadhachary GR;Wolff RA;Lee JE;Pisters PW;Crane CH;Gomez HF;Abbruzzese JL;Fleming JB;Wang H
• 通讯作者: Wang H

The emerging roles of F-box proteins in pancreatic tumorigenesis.

• DOI: 10.1016/j.semcancer.2015.09.004
• 发表时间: 2016-02
• 期刊: Seminars in cancer biology
• 影响因子: 14.5
• 作者: Hua Wang;A. Maitra;Huamin Wang

The number and ratio of positive lymph nodes affect pancreatic cancer patient survival after neoadjuvant therapy and pancreaticoduodenectomy.

• DOI: 10.1111/his.12732
• 发表时间: 2016-01
• 期刊: Histopathology
• 影响因子: 6.4
• 作者: Fischer LK;Katz MH;Lee SM;Liu L;Wang H;Varadhachary GR;Wolff RA;Lee JE;Maitra A;Roland CL;Fleming JB;Estrella J;Rashid A;Wang H
• 通讯作者: Wang H

Overexpression of protein phosphatase 4 correlates with poor prognosis in patients with stage II pancreatic ductal adenocarcinoma.

• DOI: 10.1158/1055-9965.epi-12-0223
• 发表时间: 2012-08
• 期刊: Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology
• 作者: Weng S;Wang H;Chen W;Katz MH;Chatterjee D;Lee JE;Pisters PW;Gomez HF;Abbruzzese JL;Fleming JB;Wang H
• 通讯作者: Wang H

The expression of PTEN is associated with improved prognosis in patients with ampullary adenocarcinoma after pancreaticoduodenectomy.

• DOI: 10.5858/arpa.2012-0418-oa
• 发表时间: 2013-11
• 期刊: Archives of pathology & laboratory medicine
• 影响因子: 4.6
• 作者: Shroff S;Overman MJ;Rashid A;Shroff RT;Wang H;Chatterjee D;Katz MH;Lee JE;Wolff RA;Abbruzzese JL;Fleming JB;Wang H
• 通讯作者: Wang H