Gender	Male
E-mail	zhen-qiang.pan@mssm.edu
Education and Training	Ph.D., Columbia University

Education and Training	Ph.D., Columbia University

Ubiquitin Signaling in Cancer Biology
Post-doctoral Fellows: Kenneth Wu, Antonio Sarikas, and Xinson Xu

Graduate Students: Jordan Kovacev

Covalent linkage of ubiquitin chains to cellular proteins leads to targeted degradation by the 26S proteasome, thus promoting unidirectional alteration of a divergent array of cellular processes that include cell cycle progression, signal transduction, and tumor suppression.

Central to the ubiquitination reaction are the recognition of a substrate and the recruitment of an ubiquitin-conjugating enzyme that catalyzes the transfer of ubiquitin to the target protein. This dual function is executed by a cellular activity called E3 ubiquitin protein ligase. Work from this laboratory has helped uncovering a super-family of cullin-ROC1 RING based E3 ligases. It is now widely accepted that the RING finger is the most distinct structural feature of a growing large number of cellular E3 ligases that include Parkinson disease gene product Parkin, BRCA1-BARD1 and von Hippel-Lindau tumor suppressor complexes, as well as Mdm2 that regulates p53.

We have discovered a novel E3 ligase complex containing CUL7, Fbw8, Skp1 and ROC1. Dysregulation of the CUL7 E3 Ligase has been directly linked to hereditary human diseases as cul7 germline mutations were found in patients with autosomal-recessive 3-M and Yakuts short stature syndromes, which are characterized by profound pre- and postnatal growth retardation. Recently, we have identified insulin receptor substrate 1, a critical mediator of insulin and insulin-like growth factor-1 signaling, as the proteolytic target of the CUL7 E3 ligase, suggesting a role for CUL7 as a novel growth regulator. We are currently exploring pathomechanistic insights into CUL7-linked growth retardation syndromes.

Sarikas A, Xu X, Field LJ, Pan ZQ. The Cullin7 E3 ubiquitin ligase: a novel player in growth control. Cell Cycle 2008; 7(20): 3154-3161.

Xu X, Sarikas A, Dias-Santagata DC, Dolios G, Lafontant PJ, Tsai SC, Zhu W, Nakajima H, Field LJ, Wang R, Pan ZQ. The CUL7 E3 ubiquitin ligase targets insulin receptor substrate 1 for ubiquitin-dependent degradation . Mol. Cell 2008; 30: 403-414.

Yamoah Y, Oashi T, Sarikas A, Gazdoiu S, Osman R, Pan ZQ. Auto-inhibitory regulation of SCF-mediated ubiquitination by human cullin 1's C-terminal tail. Proc.Natl. Acad. Sci USA 2005; 105(34): 12230-12235.

Gazdoiu S, Yamoah K, Wu K, Escalante CR, Tappin I, Bermudez V, Aggarwal AK, Hurwitz J, Pan ZQ. Proximity-induced activation of human Cdc34 through heterologous dimerization. Proc. Natl. Acad. Sci 2005; 102: 15053-15058.

Pan ZQ, Kentsis A, Dias DC, Yamoah K, Wu K. Nedd8 on Cullin: Building an Expressway to Protein Destruction. Oncogene 2004 3; 15(23): 1985-1997.

Wu K, Yamoah K, Dolios G, Gan-Erdene T, Tan P, Chen A, Lee CG, Wei N, Wilkinson KD, Wang R, Pan ZQ. DEN1 is a dual function protease capable of processing the C-terminus of Nedd8 deconjugating hyper-neddylated CUL1. J Biol Chem 2003; 278: 28882-28891.

Dias DC, Dolios G, Wang R, Pan ZQ. CUL7: A DOC domain-containing cullin selectively binds Skp1.Fbx29 to form an SCF-like complex. Proc Natl Acad Sci USA 2002; 99(6): 16601-16606.

Wu K, Chen A, Pan ZQ. Conjugation of Nedd8 to CUL1 enhances the ability of the ROC1-CUL1 complex to promote ubiquitin polymerization. J Biol Chem 2000; 275: 32317-32324.

Tan P, Fuchs SY, Chen A, Wu K, Gomez C, Ronai Z, Pan ZQ. Recruitment of a ROC1:Cullin1 ubiquitin ligase by Skp1 and HOS to catalyze the ubiquitination of IkBa. Mol Cell 1999; 3: 527-533.