中文版 | English

CLP36 Promotes p53-deficiency Induced Tumor Growth via Up-regulation of YAP1 Signaling

Name pinyin
LU Yixuan
School number
Mentor unit
Publication Years
Submission date
Place of Publication

The tumor suppressor protein p53 is a critical protector of genome integrity in response to biological and environmental cues. Impaired or abnormally functioning p53 contributes to initiating tumorigenesis and promoting cancer progression. Although extensive research has been devoted to revealing p53 function and regulation in cancer progression, the molecular mechanism underlying p53 deficient tumor progression remains obscure due to the complexity of p53 mutations.

CLP36, also known as PDZ and LIM domain protein 1, is a ubiquitously expressed cytoskeletal protein. As a scaffold protein, CLP36 can recruit specific signal proteins to actin and organize signaling complexes at the cytoplasm.

Furthermore, CLP36 is abnormally expressed in various malignancies and closely associated with tumor growth and metastasis. To explore the role of CLP36 in p53 deficient cancer, I examined the expression of CLP36 in p53 knockout mouse tissue and found that CLP36 is upregulated in p53 null mouse tissue. Then, with in vivo and in vitro approaches, I provided a series of evidence showing CLP36 functions as an oncoprotein in p53 deficient malignancies. Functional studies indicate that knockdown of CLP36 significantly diminished the oncogenic abilities of p53 null sarcoma cells. Also, ablation of CLP36 in p53 knockout mice confers significant protection from spontaneous tumorigenesis.

Considering the potential diagnostic and therapeutic values of CLP36 in p53 null tumor, I sought to further reveal the molecular mechanism achieving its functions. Recently, crosstalk between YAP1 function and p53 status in cancer was revealed. Loss of p53 function in cancers may be accompanied by uncontrolled YAP1 oncogenic activities. To verify whether CLP36 executes its function in p53 deficient cancer through YAP1, I detected the alterations of the levels of YAP1 after manipulation of CLP36 expression. Our results indicated that deletion of CLP36 significantly decreased the protein levels of YAP1, while re-expressing CLP36 rescued the YAP1 protein levels in CLP36 deficient cells. Since YAP1 degradation is tightly governed by phosphorylation through multiple signaling pathways, I first detected the alterations of the phosphorylation levels of YAP1 upon CLP36 inhibition. Phosphorylation of YAP1 is not significantly changed in CLP36 deficient cells. Moreover, it was reported that YAP1 degradation is

regulated by E3 ubiquitin ligases, which catalyzes YAP1 ubiquitination and ultimately leading to degradation via a proteosome-dependent manner. Treatment of proteosome inhibitor, MG132, could accumulate YAP1 in CLP36 knockdown cells, indicating that CLP36 may stabilize YAP1 predominantly via regulation of its proteasome-mediated degradation. Furthermore, I found that inhibition of E3 ligase AIP4 significantly reversed the downregulation of YAP1 levels induced by the deletion of CLP36. Mechanistically, the CLP36 function is dependent on its PDZ and ZM domain, which is essential for interacting with α-actinin. Truncated CLP36 inhibiting the α-actinin-binding activity abolishes the ability of CLP36 to stabilize YAP1 and promote oncogenic properties.

In this study, I identified the promotional role of CLP36 in p53-null tumor growth via regulating YAP1 degradation. Importantly, I proposed a new molecular regulation between CLP36 and YAP1 in p53 deficient cancer progression and demonstrated a potential diagnostic and therapeutic strategy for cancers harboring loss-of-function p53 mutation.

Training classes
Enrollment Year
Year of Degree Awarded
References List

[Adler, Jacob J., Brigitte L. Heller, Lauren R. Bringman, William P. Ranahan, Ross R. Cocklin, Mark G. Goebl, Misook Oh, Hyun Suk Lim, Robert J. Ingham, and Clark D. Wells. 2013. “Amot130 Adapts Atrophin-1 Interacting Protein 4 to Inhibit Yes-Associated Protein Signaling and Cell Growth.” Journal of Biological Chemistry 288 (21): 15181–93. Agostino, Silvia di, Giovanni Sorrentino, Eleonora Ingallina, Fabio Valenti, Maria Ferraiuolo, Silvio Bicciato, Silvano Piazza, Sabrina Strano, Giannino del Sal, and Giovanni Blandino. 2016. “ YAP Enhances the Pro‐proliferative Transcriptional Activity of Mutant P53 Proteins .” EMBO Reports 17 (2). Ahn, B. Y., R. F.G. G Saldanha-Gama, J. J. Rahn, X. Hao, J. Zhang, N. H. Dang, M. Alshehri, S. M. Robbins, and D. L. Senger. 2016a. “Glioma Invasion Mediated by the P75 Neurotrophin Receptor (P75 NTR/CD271) Requires Regulated Interaction with PDLIM1.” Oncogene 35 (11): 1411–22. Baker, Suzanne J, Sanford Markowitz, Eric R Fearon, J K Willson, and Bert Vogelstein. 1990. “Suppression of Human Colorectal Carcinoma Cell Growth by Wild-Type P53.” Science 249 (4971): 912–15.Bates, S, A C Phillips, P A Clark, F Stott, G Peters, R L Ludwig, and K H Vousden. 1998. “P14(ARF) Links the Tumour Suppressors RB and P53.” NATURE 395 (6698): 124–25.Batır, Muhammet Burak, Ergin Şahin, and Fethi Sırrı Çam. 2019. “Evaluation of the CRISPR/Cas9 Directed Mutant TP53 Gene Repairing Effect in Human Prostate Cancer Cell Line PC-3.” Molecular Biology Reports 46 (6). Beckerman, Rachel, and Carol Prives. 2010. “Transcriptional Regulation by P53.” Cold Spring Harbor Perspectives in Biology 2 (8): a000935.Bertini, Efrem, Tsutomu Oka, Marius Sudol, Sabrina Strano, and Giovanni Blandino. 2009. YAP: At the Crossroad between Transformation and Tumor Suppression. Bieging, Kathryn T., Stephano Spano Mello, and Laura D. Attardi. 2014. “Unravelling Mechanisms of P53-Mediated Tumour Suppression.” Nature Reviews Cancer. Balani, Sneha, Long v. Nguyen, and Connie J. Eaves. 2017. “Modeling the Process of Human Tumorigenesis.” Nature Communications. Nature Publishing Group.Bouaoun, Liacine, Dmitriy Sonkin, Maude Ardin, Monica Hollstein, Graham Byrnes, Jiri Zavadil, and Magali Olivier. 2016. “TP53 Variations in Human Cancers: New Lessons from the IARC TP53 Database and Genomics Data.” Human Mutation 37 (9): 865–76.Bray, Freddie, Jacques Ferlay, Isabelle Soerjomataram, Rebecca L Siegel, Lindsey A Torre, and Ahmedin Jemal. 2018. “Global Cancer Statistics 2018: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries.” CA: A Cancer Journal for Clinicians 68 (6): 394–424..Brosh, Ran, and Varda Rotter. 2009. “When Mutants Gain New Powers: News from the Mutant P53 Field.” Nature Reviews Cancer 9 (10): 701–13.Broz, D K, S S Mello, K T Bieging, D D Jiang, R L Dusek, C A Brady, A Sidow, and L D Attardi. 2013. “Global Genomic Profiling Reveals an Extensive P53-Regulated Autophagy Program Contributing to Key P53 Responses.” GENES & DEVELOPMENT 27 (9): 1016–31. Bykov, Vladimir J N, Natalia Issaeva, Alexandre Shilov, Monica Hultcrantz, Elena Pugacheva, Peter Chumakov, Jan Bergman, Klas G Wiman, and Galina Selivanova. 2002. “Restoration of the Tumor Suppressor Function to Mutant P53 by a Low-Molecular-Weight Compound.” Nature Medicine 8 (3): 282–88.Chan, Siew Wee, Chun Jye Lim, Yaan Fun Chong, Ajaybabu v. Pobbati, Caixia Huang, and Wanjin Hong. 2011. “Hippo Pathway-Independent Restriction of TAZ and YAP by Angiomotin.” Journal of Biological Chemistry 286 (9): 7018–26..Chehab, N H, A Malikzay, E S Stavridi, and T D Halazonetis. 1999. “Phosphorylation of Ser-20 Mediates Stabilization of Human P53 in Response to DNA Damage.” PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 96 (24): 13777–82. Chen, Hai Ning, Kefei Yuan, Na Xie, Kui Wang, Yan Chen, Zhao Huang, Qianhui Dou, et al. 2016. “PDLIM1 Stabilizes the E-Cadherin/b-Catenin Complex to Prevent Epithelial-Mesenchymal Transition and Metastatic Potential of Colorectal Cancer Cells.” Cancer Research 76 (5): 1122–34. Cheng, L., Z. Zhou, A. Flesken-Nikitin, I. A. Toshkov, W. Wang, J. Camps, T. Ried, and A. Y. Nikitin. 2010. “Rb Inactivation Accelerates Neoplastic Growth and Substitutes for Recurrent Amplification of CIAP1, CIAP2 and Yap1 in Sporadic Mammary Carcinoma Associated with P53 Deficiency.” Oncogene 29 (42).Chung, S W, G C Kim, S Kweon, H Lee, J U Choi, F Mahmud, H W Chang, et al. 2018. “Metronomic Oral Doxorubicin in Combination of Chk1 Inhibitor MK-8776 for P53-Deficient Breast Cancer Treatment.” Biomaterials 182: 35–43. Cottini, F, T Hideshima, C Xu, M Sattler, M Dori, L Agnelli, E ten Hacken, et al. 2014. “Rescue of Hippo Coactivator YAP1 Triggers DNA Damage-Induced Apoptosis in Hematological Cancers.” Nat Med 20 (6): 599–606. Cottini, Francesca, Teru Hideshima, Chunxiao Xu, Martin Sattler, Martina Dori, Luca Agnelli, Elisa ten Hacken, et al. 2014. “Rescue of Hippo Coactivator YAP1 Triggers DNA Damage–Induced Apoptosis in Hematological Cancers.” Nature Medicine 20 (6): 599–606. DeGregori, J, G Leone, A Miron, L Jakoi, and J R Nevins. 1997. “Distinct Roles for E2F Proteins in Cell Growth Control and Apoptosis.” PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 94 (14): 7245–50. DelBove, Jessica, Yasumichi Kuwahara, E. Lorena Mora-Blanco, Virginia Godfrey, William K. Funkhouser, Christopher D.M. Fletcher, Terry van Dyke, Charles W.M. Roberts, and Bernard E. Weissman. 2009. “Inactivation of SNF5 Cooperates with P53 Loss to Accelerate Tumor Formation in Snf5+/-;P53+/- Mice.” Molecular Carcinogenesis 48 (12): 1139–48. Donehower, Lawrence A., Michele Harvey, Betty L. Slagle, Mark J. McArthur, Charles A. Montgomery, Janet S. Butel, Allan Bradley, et al. 1991. “Mice Deficient for P53 Are Developmentally Normal but Susceptible to Spontaneous Tumours Lawrence.” Nature 356 (6366): 215–21. Donehower, Lawrence A., Thierry Soussi, Anil Korkut, Yuexin Liu, A. Schultz, M. Cardenas, X. Li, et al. 2019. “Integrated Analysis of TP53 Gene and Pathway Alterations in The Cancer Genome Atlas.” Cell Reports 28 (5): 1370-1384.e5. Elbediwy, Ahmed, Hannah Vanyai, Maria Del Carmen Diaz-De-La-Loza, David Frith, Ambrosius P. Snijders, and Barry J. Thompson. 2018. “Enigma Proteins Regulate YAP Mechanotransduction.” Journal of Cell Science 131 (22): 1–9.El-Deiry, Wafik S, Scott E Kern, Jennifer A Pietenpol, Kenneth W Kinzler, and Bert Vogelstein. 1992. “Definition of a Consensus Binding Site for P53.” Nature Genetics 1 (1): 45–49.Eliyahu, Daniel, Avraham Raz, Peter Gruss, David Givol, and Moshe Oren. 1984. “Participation of P53 Cellular Tumour Antigen in Transformation of Normal Embryonic Cells.” Nature 312 (5995): 646–49.Embree-Ku, Michelle, and Kim Boekelheide. 2002. “FasL Deficiency Enhances the Development of Tumors in P53+/- Mice.” Toxicologic Pathology 30 (6): 705–13. Escoll, M., R. Gargini, A. Cuadrado, I. M. Antón, and F. Wandosell. 2017. “Mutant P53 Oncogenic Functions in Cancer Stem Cells Are Regulated by WIP through YAP/TAZ.” Oncogene 36 (25).Finlay, Cathy A, Philip W Hinds, and Arnold J Levine. 1989. “The P53 Proto-Oncogene Can Act as a Suppressor of Transformation.” Cell 57 (7): 1083–93.Fromentel, Claude Caron de, and Thierry Soussi. 1992. “TP53 Tumor Suppressor Gene: A Model for Investigating Human Mutagenesis.” Genes, Chromosomes and Cancer 4 (1): 1–15.Frum, R A, and S R Grossman. 2014. “Mechanisms of Mutant P53 Stabilization in Cancer.” Subcell Biochem 85: 187–97. Fullenkamp, Colleen A., Sarah L. Hall, Omar I. Jaber, Brittany L. Pakalniskis, Erica C. Savage, Johanna M. Savage, Georgina K. Ofori-Amanfo, Allyn M. Lambertz, Stephanie D. Ivins, Christopher S. Stipp, et al. 2016. “TAZ and YAP Are Frequently Activated Oncoproteins in Sarcomas.” Oncotarget 7 (21): 30094–108. Goh, Amanda M, Cynthia R Coffill, and David P Lane. 2011. “The Role of Mutant P53 in Human Cancer.” The Journal of Pathology 223 (2): 116–26.Gupta, Prachi, Shankar Suman, Manisha Mishra, Sanjay Mishra, Nidhi Srivastava, Vijay Kumar, Pradhyumna Kumar Singh, and Yogeshwer Shukla. 2016. “Autoantibodies against TYMS and PDLIM1 Proteins Detected as Circulatory Signatures in Indian Breast Cancer Patients.” Proteomics - Clinical Applications 10 (5): 564–73.Gurpinar, Evrim, and Karen H Vousden. 2015. “Hitting Cancers’ Weak Spots: Vulnerabilities Imposed by P53 Mutation.” Trends in Cell Biology 25 (8): 486–95.Hao, Yawei, Alex Chun, Kevin Cheung, Babak Rashidi, and Xiaolong Yang. 2008. “Tumor Suppressor LATS1 Is a Negative Regulator of Oncogene YAP.” Journal of Biological Chemistry 283 (9): 5496–5509. Harada, N, Y Watanabe, Y Yoshimura, H Sakumoto, F Makishima, M Tsuchiya, K Nakanishi, M Nakanishi, and Y Aoki. 2011. “Identification of a Checkpoint Modulator with Synthetic Lethality to P53 Mutants.” Anticancer Drugs 22 (10): 986–94. Haupt, Susan, and Ygal Haupt. 2004. “Manipulation of the Tumor Suppressor P53 for Potentiating Cancer Therapy.” In , 4th ed., 14:244–52. Elsevier.Haupt, Y, R Maya, A Kazaz, and M Oren. 1997. “Mdm2 Promotes the Rapid Degradation of P53.” NATURE 387 (6630): 296–99. Hayes, Josie, Pier Paolo Peruzzi, and Sean Lawler. 2014. “MicroRNAs in Cancer: Biomarkers, Functions and Therapy.” Trends in Molecular Medicine. Heng, B C, X Zhang, D Aubel, Y Bai, X Li, Y Wei, M Fussenegger, and X Deng. 2021. “An Overview of Signaling Pathways Regulating YAP/TAZ Activity.” Cell Mol Life Sci 78 (2): 497–512.Heng, Boon Chin, Xuehui Zhang, Dominique Aubel, Yunyang Bai, Xiaochan Li, Yan Wei, Martin Fussenegger, and Xuliang Deng. 2021. “An Overview of Signaling Pathways Regulating YAP/TAZ Activity.” Cellular and Molecular Life Sciences. Holden, Jeffrey K, and Christian N Cunningham. 2018. “Targeting the Hippo Pathway and Cancer through the TEAD Family of Transcription Factors.” Cancers 10 (3): 81.Hollstein, Monica, David Sidransky, Bert Vogelstein, and C Harris Curtis. 1991. “P53 Mutations in Human Cancers.” Science 253 (5015): 49–53. Honda, R, and H Yasuda. 1999. “Association of P19(ARF) with Mdm2 Inhibits Ubiquitin Ligase Activity of Mdm2 for Tumor Suppressor P53.” EMBO JOURNAL 18 (1): 22–27. Hong, Su-Hyung. 2005. “Identification of CLP36 as a Tumor Antigen That Induces an Antibody Response in Pancreatic Cancer.” Cancer Research and Treatment 37 (1): 71. Huang, Zhao, Jian-kang Kang Zhou, Kui Wang, Haining Chen, Siyuan Qin, Jiayang Liu, Maochao Luo, et al. 2020. “PDLIM1 Inhibits Tumor Metastasis Through Activating Hippo Signaling in Hepatocellular Carcinoma.” Hepatology 71 (5): 1643–59. Jacks, Tyler, Lee Remington, Bart O. Williams, Earlene M. Schmitt, Schlomit Halachmi, Roderick T. Bronson, and Robert A. Weinberg. 1994. “Tumor Spectrum Analysis in P53-Mutant Mice.” Current Biology 4 (1): 1–7. Jabbour, Elias, and Hagop Kantarjian. 2018. “Chronic Myeloid Leukemia: 2018 Update on Diagnosis, Therapy and Monitoring.” American Journal of Hematology 93 (3).Jenkins, J R, K Rudge, and G A Currie. 1984. “Cellular Immortalization by a CDNA Clone Encoding the Transformation-Associated Phosphoprotein P53.” Nature 312 (5995): 651–54.Jenkins, L M M, S R Durell, S J Mazur, and E Appella. 2012. “P53 N-Terminal Phosphorylation: A Defining Layer of Complex Regulation.” CARCINOGENESIS 33 (8): 1441–49. Johnston, Angela L.M., Xueqing Lun, Jennifer J. Rahn, Abdelhamid Liacini, Limei Wang, Mark G. Hamilton, Ian F. Parney, et al. 2007. “The P75 Neurotrophin Receptor Is a Central Regulator of Glioma Invasion.” PLoS Biology 5 (8). Kaiser, Alyssa M., and Laura D. Attardi. 2018. “Deconstructing Networks of P53-Mediated Tumor Suppression in vivo.” Cell Death and Differentiation 25 (1): 93–103. Kapoor, A, W Yao, H Ying, S Hua, A Liewen, Q Wang, Y Zhong, et al. 2014. “Yap1 Activation Enables Bypass of Oncogenic Kras Addiction in Pancreatic Cancer.” Cell 158 (1): 185–97.Kapoor, Avnish, Wantong Yao, Haoqiang Ying, Sujun Hua, Alison Liewen, Qiuyun Wang, Yi Zhong, et al. 2014. “Yap1 Activation Enables Bypass of Oncogenic KRAS Addiction in Pancreatic Cancer.” Cell 158 (1): 185–97. Kastan, Michael B., and Jiri Bartek. 2004. “Cell-Cycle Checkpoints and Cancer.” Nature. Kastan, Michael B, and Elijahu Berkovich. 2007. “P53: A Two-Faced Cancer Gene.” Nature Cell Biology 9 (5): 489–91.Kastenhuber, Edward R., and Scott W. Lowe. 2017. “Putting P53 in Context.” Cell 170 (6): 1062–78.Knudson, C. Michael, Geoffrey M. Johnson, Yuan Lin, and Stanley J. Korsmeyer. 2001. “Bax Accelerates Tumorigenesis in P53-Deficient Mice.” Cancer Research 61 (2): 659–65.Kodaka, Manami, and Yutaka Hata. 2015. “The Mammalian Hippo Pathway: Regulation and Function of YAP1 and TAZ.” Cellular and Molecular Life Sciences 72 (2): 285–306.Kotaka, Masayo, Sawa Kostin, Sai‐ming Ngai, Kwok‐keung Chan, Yee‐man Lau, Simon M Y Lee, Hoi‐yeung Li, Enders K O Ng, Jutta Schaper, and Stephen K W Tsui. 2000. “Interaction of HCLIM1, an Enigma Family Protein, with Α‐actinin 2.” Journal of Cellular Biochemistry 78 (4): 558–65.Kubbutat, M H G, S N Jones, and K H Vousden. 1997. “Regulation of P53 Stability by Mdm2.” NATURE 387 (6630): 299–303.Lane, D. P., and L. v. Crawford. 1979. “T Antigen Is Bound to a Host Protein in SY40-Transformed Cells
[19].” Nature. Lee, Y H, and G G Song. 2019. “MicroRNA-370-3p Inhibits Cell Proliferation and Induces Chronic Myelogenous Leukemia Cell Apoptosis by Suppressing PDLIM1/Wnt/β-Catenin Signaling.” Neoplasma 60 (5): 607–16. Leko, Vid, and Steven A. Rosenberg. 2020. “Identifying and Targeting Human Tumor Antigens for T Cell-Based Immunotherapy of Solid Tumors.” Cancer Cell. Leroy, B, L Girard, A Hollestelle, J D Minna, A F Gazdar, and T Soussi. 2014. “Analysis of TP53 Mutation Status in Human Cancer Cell Lines: A Reassessment.” Hum Mutat 35 (6): 756–65. Levine, Arnold J. 2020. “P53: 800 Million Years of Evolution and 40 Years of Discovery.” Nature Reviews Cancer 20 (8): 471–80. Li, Hui, Zhenglan Huang, Miao Gao, Ningshu Huang, Zhenhong Luo, Huawei Shen, Xin Wang, Teng Wang, Jing Hu, and Wenli Feng. 2016. “Inhibition of YAP Suppresses CML Cell Proliferation and Enhances Efficacy of Imatinib in Vitro and in vivo.” Li, Tongyuan, Xiangyu Liu, Le Jiang, James Manfredi, Shan Zha, and Wei Gu. 2016. “Loss of P53-Mediated Cell-Cycle Arrest, Senescence and Apoptosis Promotes Genomic Instability and Premature Aging.” Oncotarget 7 (11): 11838–49. Li, Xiaomin, Jianjun Wang, Chao Zhang, Chun Lin, Jianming Zhang, Wei Zhang, Wenjuan Zhang, Yanxia Lu, Lin Zheng, and Xuenong Li. 2018. “Circular RNA CircITGA7 Inhibits Colorectal Cancer Growth and Metastasis by Modulating the Ras Pathway and Upregulating Transcription of Its Host Gene ITGA7.” Journal of Pathology 246 (2). Liang, Xingqun, Qiang Zhou, Xiaodong Li, Yunfu Sun, Min Lu, Nancy Dalton, John Ross, and Ju Chen. 2005. “PINCH1 Plays an Essential Role in Early Murine Embryonic Development but Is Dispensable in Ventricular Cardiomyocytes.” Molecular and Cellular Biology 25 (8): 3056–62. Liu, Y, X Zhang, C Han, G Wan, X Huang, C Ivan, D Jiang, et al. 2015. “TP53 Loss Creates Therapeutic Vulnerability in Colorectal Cancer.” Nature 520 (7549): 697–701. Liu Y, Zhang X, Han C, Wan G, Huang X, Ivan C, Jiang D, Rodriguez-Aguayo C, Lopez-Berestein G, Rao PH, et al. (2015). TP53 loss creates therapeutic vulnerability in colorectal cancer. Nature 520, 697–701.Liu, Z., Y. Zhan, Y. Tu, K. Chen, Z. Liu, and C. Wu. 2015. “PDZ and LIM Domain Protein 1(PDLIM1)/CLP36 Promotes Breast Cancer Cell Migration, Invasion and Metastasis through Interaction with α-Actinin.” Oncogene 34 (10): 1300–1311. Liu, Zhongmin, Simone Monika Blattner, Yizeng Tu, Robert Tisherman, James H. Wang, Maria Pia Rastaldi, Matthias Kretzler, and Chuanyue Wu. 2011. “α-Actinin-4 and CLP36 Protein Deficiencies Contribute to Podocyte Defects in Multiple Human Glomerulopathies.” Journal of Biological Chemistry 286 (35): 30795–805. Louis, David N., Arie Perry, Guido Reifenberger, Andreas von Deimling, Dominique Figarella-Branger, Webster K. Cavenee, Hiroko Ohgaki, Otmar D. Wiestler, Paul Kleihues, and David W. Ellison. 2016. “The 2016 World Health Organization Classification of Tumors of the Central Nervous System: A Summary.” Acta Neuropathologica. Low, Lionel, Angeline Goh, Joanna Koh, Samantha Lim, and Cheng I. Wang. 2019. “Targeting Mutant P53-Expressing Tumours with a T Cell Receptor-like Antibody Specific for a Wild-Type Antigen.” Nature Communications 10 (1). Lowe, S W, and C J Sherr. 2003. “Tumor Suppression by Ink4a-Arf: Progress and Puzzles.” CURRENT OPINION IN GENETICS & DEVELOPMENT 13 (1): 77–83. Lozano, G. 2010. “Mouse Models of P53 Functions.” Cold Spring Harb Perspect Biol 2 (4): a001115. Lozano, Guillermina. 2007. “The Oncogenic Roles of P53 Mutants in Mouse Models.” Current Opinion in Genetics & Development 17 (1): 66–70.Lujambio, A, L Akkari, J Simon, D Grace, D F Tschaharganeh, J E Bolden, Z Zhao, et al. 2013. “Non-Cell-Autonomous Tumor Suppression by P53.” CELL 153 (2): 449–60. Malkin, David, Frederick P Li, Louise C Strong, Joseph F Fraumeni, Camille E Nelson, David H Kim, Jayne Kassel, Magdalena A Gryka, Farideh Z Bischoff, and Michael A Tainsky. 1990. “Germ Line P53 Mutations in a Familial Syndrome of Breast Cancer, Sarcomas, and Other Neoplasms.” Science 250 (4985): 1233–38.Mao, Jian-Hua, Jesus Perez-Losada, Di Wu, Reyno Delrosario, Ryosuke Tsunematsu, Keiichi I Nakayama, Ken Brown, Sheila Bryson, and Allan Balmain. 2004. “Fbxw7/Cdc4 Is a P53-Dependent, Haploinsufficient Tumour Suppressor Gene.”Mao, Yaopan, Shuguo Sun, and Kenneth D Irvine. 2017a. “Role and Regulation of Yap in KrasG12D-Induced Lung Cancer.” Oncotarget 8 (67): 110877.Meek, D W, and C W Anderson. 2009. “Posttranslational Modification of P53: Cooperative Integrators of Function.” COLD SPRING HARBOR PERSPECTIVES IN BIOLOGY 1 (6). Mello, Stephano S, and Laura D Attardi. 2018. “Deciphering P53 Signaling in Tumor Suppression.” Current Opinion in Cell Biology 51: 65–72.Mello, Stephano S., Liz J. Valente, Nitin Raj, Jose A. Seoane, Brittany M. Flowers, Jacob McClendon, Kathryn T. Bieging-Rolett, et al. 2017. “A P53 Super-Tumor Suppressor Reveals a Tumor Suppressive P53-Ptpn14-Yap Axis in Pancreatic Cancer.” Cancer Cell 32 (4): 460-473.e6. Meng, Zhipeng, Toshiro Moroishi, and Kun Liang Guan. 2016. “Mechanisms of Hippo Pathway Regulation.” Genes and Development 30 (1): 1–17..115.Michaloglou, Chrysiis, Waltraut Lehmann, Typhaine Martin, Clara Delaunay, Andreas Hueber, Louise Barys, Honglin Niu, et al. 2013. “The Tyrosine Phosphatase PTPN14 Is a Negative Regulator of YAP Activity.” PLoS ONE 8 (4). Min, J-N, L. Huang, D. B. Zimonjic, D. Moskophidis, and N. F. Mivechi. 2007. “Selective Suppression of Lymphomas by Functional Loss of Hsf1 in a P53-Deficient Mouse Model for Spontaneous Tumors.” Oncogene 26 (35): 5086–97. Morandell, Sandra, H Christian Reinhardt, Ian G Cannell, Jacob S Kim, Daniela M Ruf, Tanya Mitra, Anthony D Couvillon, Tyler Jacks, and Michael B Yaffe. 2013. “A Reversible Gene-Targeting Strategy Identifies Synthetic Lethal Interactions between MK2 and P53 in the DNA Damage Response in vivo.” Cell Reports 5 (4): 868–77.Muller, Patricia A J, and Karen H Vousden. 2013a. “P53 Mutations in Cancer.” Nature Cell Biology 15 (1): 2–8.———. 2014. “Mutant P53 in Cancer: New Functions and Therapeutic Opportunities.” Cancer Cell 25 (3): 304–17.Mulligan LM, Matlashewski GJ, Scrable HJ, and Cavenee WK (1990). Mechanisms of p53 loss in human sarcomas. Proc Natl Acad Sci U S A 87, 5863–5867.Nguyen, Thanh Hung, and Jan Michael Kugler. 2018. “Ubiquitin-Dependent Regulation of the Mammalian Hippo Pathway: Therapeutic Implications for Cancer.” Cancers 10 (4).O’connor, A.J. Kwilasz, and O’connor. 2016. “A Time for YAP1: Tumorigenesis, Immunosuppression and Targeted Therapy.” Physiology & Behavior 176 (1): 139–48. O’Gorman, S, N A Dagenais, M Qian, and Y Marchuk. 1997. “Protamine-Cre Recombinase Transgenes Efficiently Recombine Target Sequences in the Male Germ Line of Mice, but Not in Embryonic Stem Cells.” Proceedings of the National Academy of Sciences of the United States of America 94 (26): 14602–7. Oka, Tsutomu, and Marius Sudol. 2009. “Nuclear Localization and Pro-Apoptotic Signaling of YAP2 Require Intact PDZ-Binding Motif.” Genes to Cells 14 (5). OLINER, J D, J A PIETENPOL, S THIAGALINGAM, J GVURIS, K W KINZLER, and B VOGELSTEIN. 1993. “ONCOPROTEIN MDM2 CONCEALS THE ACTIVATION DOMAIN OF TUMOR SUPPRESSOR-P53.” NATURE 362 (6423): 857–60. Olivier, Magali, Monica Hollstein, and Pierre Hainaut. 2010a. TP53 Mutations in Human Cancers: Origins, Consequences, and Clinical Use. Cold Spring Harbor Perspectives in Biology. Vol. 2. Cold Spring Harbor Lab. Oren, Moshe, and Varda Rotter. 2010. “Mutant P53 Gain-of-Function in Cancer.” Cold Spring Harbor Perspectives in Biology 2 (2): a001107.Origanti, Sofia, S R Cai, Amir Z Munir, Lynn S White, and Helen Piwnica-Worms. 2013. “Synthetic Lethality of Chk1 Inhibition Combined with P53 and/or P21 Loss during a DNA Damage Response in Normal and Tumor Cells.” Oncogene 32 (5): 577–88.Palacios, Gustavo, Flaminia Talos, Alice Nemajerova, Ute M. Moll, and Oleksi Petrenko. 2008. “E2F1 Plays a Direct Role in Rb Stabilization and P53-Independent Tumor Suppression.” Cell Cycle 7 (12): 1776–81. Parada, Luis F, Hartmut Land, Robert A Weinberg, David Wolf, and Varda Rotter. 1984. “Cooperation between Gene Encoding P53 Tumour Antigen and Ras in Cellular Transformation.” Nature 312 (5995): 649–51.Petitjean, A, E Mathe, S Kato, C Ishioka, S v Tavtigian, P Hainaut, and M Olivier. 2007. “Impact of Mutant P53 Functional Properties on TP53 Mutation Patterns and Tumor Phenotype: Lessons from Recent Developments in the IARC TP53 Database.” Hum Mutat 28 (6): 622–29. Pichot, Christina S., Constadina Arvanitis, Sean M. Hartig, Samuel A. Jensen, John Bechill, Saad Marzouk, Jindan Yu, Jeffrey A. Frost, and Seth J. Corey. 2010. “Cdc42-Interacting Protein 4 Promotes Breast Cancer Cell Invasion and Formation of Invadopodia through Activation of N-WASp.” Cancer Research 70 (21). Pitteri, S J, K S Kelly-Spratt, K E Gurley, J Kennedy, T B Buson, A Chin, H Wang, et al. 2011. “Tumor Microenvironment-Derived Proteins Dominate the Plasma Proteome Response during Breast Cancer Induction and Progression.” Cancer Res 71 (15): 5090–5100. Rai, Alin, David W Greening, Maoshan Chen, Rong Xu, Hong Ji, and Richard J Simpson. 2019. “Exosomes Derived from Human Primary and Metastatic Colorectal Cancer Cells Contribute to Functional Heterogeneity of Activated Fibroblasts by Reprogramming Their Proteome.” Proteomics 19 (8): e1800148. Raj, Nitin, and Rakesh Bam. 2019. “Reciprocal Crosstalk Between YAP1/Hippo Pathway and the P53 Family Proteins: Mechanisms and Outcomes in Cancer.” Frontiers in Cell and Developmental Biology 7 (August): 1–10. Robles, Ana I, and Curtis C Harris. 2010. “Clinical Outcomes and Correlates of TP53 Mutations and Cancer.” Cold Spring Harbor Perspectives in Biology 2 (3): a001016.Rodríguez, Carolyn I., Frank Buchholz, Jenna Galloway, Reynaldo Sequerra, Jocelyn Kasper, Ramses Ayala, A. Francis Stewart, and Susan M. Dymecki. 2000. “High-Efficiency Deleter Mice Show That FLPe Is an Alternative to Cre- LoxP.” Nature Genetics 25 (2): 139–40. Shao, Diane D., Wen Xue, Elsa B. Krall, Arjun Bhutkar, Federica Piccioni, Xiaoxing Wang, Anna C. Schinzel, et al. 2014. “KRAS and YAP1 Converge to Regulate EMT and Tumor Survival.” Cell 158 (1): 171–84. Shaw, P, R Bovey, S Tardy, R Sahli, B Sordat, and J Costa. 1992. “Induction of Apoptosis by Wild-Type P53 in a Human Colon Tumor-Derived Cell Line.” Proc Natl Acad Sci U S A 89 (10): 4495–99. Shieh, S Y, M Ikeda, Y Taya, and C Prives. 1997. “DNA Damage-Induced Phosphorylation of P53 Alleviates Inhibition by MDM2.” CELL 91 (3): 325–34. Siegel, Rebecca L., Kimberly D. Miller, and Ahmedin Jemal. 2019a. “Cancer Statistics, 2019.” CA: A Cancer Journal for Clinicians 69 (1): 7–34. Smith, Martin L, and Albert J Fornace Jr. 1995. “Genomic Instability and the Role of P53 Mutations in Cancer Cells.” Current Opinion in Oncology 7 (1): 69–75.Soussi, T, and K G Wiman. 2015. “TP53: An Oncogene in Disguise.” Cell Death & Differentiation 22 (8): 1239–49.Stein, Yan, Varda Rotter, and Ronit Aloni-Grinstein. 2019. “Gain-of-Function Mutant P53: All the Roads Lead to Tumorigenesis.” International Journal of Molecular Sciences 20 (24). Strano, Sabrina, Stefania Dell’Orso, Adriana Maria Mongiovi, Olimpia Monti, Eleonora Lapi, Silvia di Agostino, Giulia Fontemaggi, and Giovanni Blandino. 2007. “Mutant P53 Proteins: Between Loss and Gain of Function.” Head & Neck: Journal for the Sciences and Specialties of the Head and Neck 29 (5): 488–96.Synoradzki, Kamil Jozef, Ewa Bartnik, Anna M. Czarnecka, Michał Fiedorowicz, Wiktoria Firlej, Anna Brodziak, Agnieszka Stasinska, Piotr Rutkowski, and Paweł Grieb. 2021. “TP53 in Biology and Treatment of Osteosarcoma.” Cancers 13 (17): 4284.Tamura, Naoaki, Koji Ohno, Taiichi Katayama, Naohiro Kanayama, and Kohji Sato. 2007. “The PDZ-LIM Protein CLP36 Is Required for Actin Stress Fiber Formation and Focal Adhesion Assembly in BeWo Cells.” Biochemical and Biophysical Research Communications 364 (3): 589–94. Tang, Dong E., Yong Dai, Lie Wen Lin, Yong Xu, Dong Zhou Liu, Xiao Ping Hong, Hao Wu Jiang, and Song Hui Xu. 2019. “STUB1 Suppresseses Tumorigenesis and Chemoresistance through Antagonizing YAP1 Signaling.” Cancer Science 110 (10): 3145–56.Tao, Luwei, Dongxi Xiang, Ying Xie, Roderick T. Bronson, and Zhe Li. 2017. “Induced P53 Loss in Mouse Luminal Cells Causes Clonal Expansion and Development of Mammary Tumours.” Nature Communications 8. Tarapore, Pheruza, and Kenji Fukasawa. 2002. “Loss of P53 and Centrosome Hyperamplification.” Oncogene 21 (40): 6234–40.Thompson, Barry J. 2020. “YAP/TAZ: Drivers of Tumor Growth, Metastasis, and Resistance to Therapy.” BioEssays 42 (5): 1–16. Toguchida J. (2016) Genetics of osteosarcoma. Chapter 1 in Osteosarcoma. Editors Ueda T. and Kawai A. Springer (Japan) p.3-18. Tojkander, Sari, Gergana Gateva, and Pekka Lappalainen. 2012. “Actin Stress Fibers - Assembly, Dynamics and Biological Roles.” Journal of Cell Science 125 (8). Tongyang, L, G Haiqiang, Z Meiyan, H Yingze, J Shuting, L Ying, and Z Jihong. 2015. “[Synthetic Lethal Genes to Mutant P53].” Yi Chuan 37 (4): 321–26. Totaro, Antonio, Tito Panciera, and Stefano Piccolo. 2019. “YAP/TAZ Upstream Signals and Downstream Responses” 20 (8): 888–99. Tu, Kangsheng, Wei Yang, Chao Li, Xin Zheng, Zhongtang Lu, Cheng Guo, Yingmin Yao, and Qingguang Liu. 2014. “Fbxw7 Is an Independent Prognostic Marker and Induces Apoptosis and Growth Arrest by Regulating YAP Abundance in Hepatocellular Carcinoma.” Molecular Cancer 13 (1): 1–13. Uhlen, M., L. Fagerberg, B. M. Hallstrom, C. Lindskog, P. Oksvold, A. Mardinoglu, A. Sivertsson, et al. 2015. “Tissue-Based Map of the Human Proteome.” Science 347 (6220). Vallenius, Tea. 2013. “Actin Stress Fibre Subtypes in Mesenchymal-Migrating Cells.” Open Biology 3 (JUN). Vallenius, Tea, Keijo Luukko, and Tomi P. Mäkelä. 2000. “CLP-36 PDZ-LIM Protein Associates with Nonmuscle α-Actinin-1 and α- Actinin-4.” Journal of Biological Chemistry 275 (15): 11100–105. Vallenius, Tea, and Tomi P Mäkelä. 2002. “Clik1: A Novel Kinase Targeted to Actin Stress Fibers by the CLP-36 PDZ-LIM Protein.” Journal of Cell Science 115 (10): 2067–73.Vassilev, Lyubomir T, Binh T Vu, Bradford Graves, Daisy Carvajal, Frank Podlaski, Zoran Filipovic, Norman Kong, Ursula Kammlott, Christine Lukacs, and Christian Klein. 2004. “In vivo Activation of the P53 Pathway by Small-Molecule Antagonists of MDM2.” Science 303 (5659): 844–48.Velthuis, Aartjan J.W. te, Tadamoto Isogai, Lieke Gerrits, and Christoph P. Bagowski. 2007. “Insights into the Molecular Evolution of the PDZ/LIM Family and Identification of a Novel Conserved Protein Motif.” PLoS ONE 2 (2): e189. Ventura, Andrea, David G. Kirsch, Margaret E. McLaughlin, David A. Tuveson, Jan Grimm, Laura Lintault, Jamie Newman, Elizabeth E. Reczek, Ralph Weissleder, and Tyler Jacks. 2007. “Restoration of P53 Function Leads to Tumour Regression in vivo.” Nature 445 (7128): 661–65. Vittoria, Marc A., Elizabeth M. Shenk, Kevin P. O’Rourke, Amanda F. Bolgioni, Sanghee Lim, Victoria Kacprzak, Ryan J. Quinton, and Neil J. Ganem. 2018. “A Genome-Wide MicroRNA Screen Identifies Regulators of Tetraploid Cell Proliferation.” Molecular Biology of the Cell 29 (14). Wang, Haiwei, Xinrui Wang, Liangpu Xu, Yingying Lin, Ji Zhang, and Hua Cao. 2021. “Low Expression of CDHR1 Is an Independent Unfavorable Prognostic Factor in Glioma.” Journal of Cancer 12 (17): 5193–5205.Wang, J.-J, K.-F Lei, and F Han. n.d. “Tumor Microenvironment: Recent Advances in Various Cancer Treatments.”Wang, Li Mei, Jennifer J. Rahn, Xue Qing Lun, Beichen Sun, John J.P. Kelly, Samuel Weiss, Stephen M. Robbins, Peter A. Forsyth, and Donna L. Senger. 2008. “Gamma-Secretase Represents a Therapeutic Target for the Treatment of Invasive Glioma Mediated by the P75 Neurotrophin Receptor.” PLoS Biology 6 (11). Wang, Xiaosheng, and Richard Simon. 2013. “Identification of Potential Synthetic Lethal Genes to P53 Using a Computational Biology Approach.” BMC Medical Genomics 6 (1): 1–10.Wang, Zebin, Yu Zheng, Hyun Jung Park, Jing Li, Janai R. Carr, Yi-ju Chen, Megan M. Kiefer, et al. 2013. “Targeting FoxM1 Effectively Retards P53-Null Lymphoma and Sarcoma.” Molecular Cancer Therapeutics 12 (5): 759–67. Wanjala, Jackie, Barry S. Taylor, Caren Chapinski, Haley Hieronymus, John Wongvipat, Yu Chen, Gouri J. Nanjangud, et al. 2015. “Identifying Actionable Targets through Integrative Analyses of GEM Model and Human Prostate Cancer Genomic Profiling.” Molecular Cancer Therapeutics 14 (1). Weber, J D, L J Taylor, M F Roussel, C J Sherr, and D Bar-Sagi. 1999. “Nucleolar Arf Sequesters Mdm2 and Activates P53.” NATURE CELL BIOLOGY 1 (1): 20–26. Weidle, Ulrich H, Daniela Maisel, and Dirk Eick. 2011. “Synthetic Lethality-Based Targets for Discovery of New Cancer Therapeutics.” Cancer Genomics & Proteomics 8 (4): 159–71.Wilczynska, A., and M. Bushell. 2015. “The Complexity of MiRNA-Mediated Repression.” Cell Death and Differentiation. Wolf, David, Nicholas Harris, and Varda Rotter. 1984. “Reconstitution of P53 Expression in a Nonproducer Ab-MuLV-Transformed Cell Line by Transfection of a Functional P53 Gene.” Cell 38 (1): 119–26.Xue, W, L Zender, C Miething, R A Dickins, E Hernando, V Krizhanovsky, C Cordon-Cardo, and S W Lowe. 2007. “Senescence and Tumour Clearance Is Triggered by P53 Restoration in Murine Liver Carcinomas.” NATURE 445 (7128): 656–60. YANG, ZHI, MING ZHANG, KE XU, LIN LIU, WEI-KUN HOU, YUAN-ZHEN CAI, PENG XU, and JIAN-FENG YAO. 2014. “Knockdown of YAP1 Inhibits the Proliferation of Osteosarcoma Cells in Vitro and in Vivo.” Oncology Reports 32 (3): 1265–72.Yao, Fan, Zhicheng Zhou, Jongchan Kim, Qinglei Hang, Zhenna Xiao, Baochau N. Ton, Liang Chang, et al. 2018. “SKP2- and OTUD1-Regulated Non-Proteolytic Ubiquitination of YAP Promotes YAP Nuclear Localization and Activity.” Nature Communications 9 (1): 1–16. Ye, Shuai, Matthew A. Lawlor, Adrian Rivera-Reyes, Shaun Egolf, Susan Chor, Koreana Pak, Gabrielle E. Ciotti, et al. 2018. “YAP1-Mediated Suppression of USP31 Enhances NFkB Activity to Promote Sarcomagenesis.” Cancer Research 78 (10): 2705–20.Yi, Xuan, Xueqiang Deng, Yanzhi Zhao, Binbin Deng, Jianyong Deng, Huimin Fan, Yunyan Du, and Liang Hao. 2020. “Ubiquitin-like Protein FAT10 Promotes Osteosarcoma Growth by Modifying the Ubiquitination and Degradation of YAP1.” Experimental Cell Research 387 (2): 111804. Yu, Wan-Ni, Veronique Nogueira, Arya Sobhakumari, Krushna C. Patra, Prashanth T. Bhaskar, and Nissim Hay. 2015. “Systemic Akt1 Deletion after Tumor Onset in P53−/− Mice Increases Lifespan and Regresses Thymic Lymphoma Emulating P53 Restoration.” Cell Reports 12 (4): 610–21. Yuan, M, V Tomlinson, R Lara, D Holliday, C Chelala, T Harada, R Gangeswaran, et al. 2008a. “Yes-Associated Protein (YAP) Functions as a Tumor Suppressor in Breast.” Cell Death Differ 15 (11): 1752–59. Zanconato, Francesca, Michelangelo Cordenonsi, and Stefano Piccolo. 2016a. “YAP/TAZ at the Roots of Cancer.” Cancer Cell 29 (6): 783–803. Zhan, Hengji, Haibiao Xie, Qun Zhou, Yuchen Liu, and Weiren Huang. 2018. “Synthesizing a Genetic Sensor Based on CRISPR-Cas9 for Specifically Killing P53-Deficient Cancer Cells.” ACS Synthetic Biology 7 (7). Zhan, T., N. Rindtorff, and M. Boutros. 2017. “Wnt Signaling in Cancer.” Oncogene 36 (11): 1461–73. Zhang, Jianmin, Gromoslaw A. Smolen, and Daniel A. Haber. 2008. “Negative Regulation of YAP by LATS1 Underscores Evolutionary Conservation of the Drosophila Hippo Pathway.” Cancer Research 68 (8): 2789–94. Zhang, Y P, and Y Xiong. 1999. “Mutations in Human ARF Exon 2 Disrupt Its Nucleolar Localization and Impair Its Ability to Block Nuclear Export of MDM2 and P53.” MOLECULAR CELL 3 (5): 579–91. ———. 2001. “Control of P53 Ubiquitination and Nuclear Export by MDM2 and ARF.” CELL GROWTH & DIFFERENTIATION 12 (4): 175–86.Zhao, B, X Ye, J Yu, L Li, W Li, S Li, J Yu, et al. 2008. “TEAD Mediates YAP-Dependent Gene Induction and Growth Control.” Genes Dev 22 (14): 1962–71. Zhao, Bin, Li Li, Karen Tumaneng, Cun Yu Wang, and Kun Liang Guan. 2010. “A Coordinated Phosphorylation by Lats and CK1 Regulates YAP Stability through SCFβ-TRCP.” Genes and Development 24 (1): 72–85.

Data Source
Document TypeThesis
DepartmentDepartment of Biology
Recommended Citation
GB/T 7714
Lu YX. CLP36 Promotes p53-deficiency Induced Tumor Growth via Up-regulation of YAP1 Signaling[D]. 香港. 香港大学,2022.
Files in This Item:
File Name/Size DocType Version Access License
11750022-卢羿璇-生物系.pdf(82171KB) Restricted Access--Fulltext Requests
Related Services
Recommend this item
Usage statistics
Export to Endnote
Export to Excel
Export to Csv
Altmetrics Score
Google Scholar
Similar articles in Google Scholar
[卢羿璇]'s Articles
Baidu Scholar
Similar articles in Baidu Scholar
[卢羿璇]'s Articles
Bing Scholar
Similar articles in Bing Scholar
[卢羿璇]'s Articles
Terms of Use
No data!
Social Bookmark/Share
No comment.

Items in the repository are protected by copyright, with all rights reserved, unless otherwise indicated.