Structural studies of UBXN2A and mortalin interaction and the putative role of silenced UBXN2A in preventing response to chemotherapy

  title={Structural studies of UBXN2A and mortalin interaction and the putative role of silenced UBXN2A in preventing response to chemotherapy},
  author={S. Sane and A. Abdullah and M. Nelson and Hongmin Wang and S. Chauhan and S. S. Newton and K. Rezvani},
  journal={Cell Stress and Chaperones},
Overexpression of the oncoprotein mortalin in cancer cells and its protein partners enables mortalin to promote multiple oncogenic signaling pathways and effectively antagonize chemotherapy-induced cell death. A UBX-domain-containing protein, UBXN2A, acts as a potential mortalin inhibitor. This current study determines whether UBXN2A effectively binds to and occupies mortalin’s binding pocket, resulting in a direct improvement in the tumor’s sensitivity to chemotherapy. Molecular modeling of… Expand
UBXN2A enhances CHIP‐mediated proteasomal degradation of oncoprotein mortalin‐2 in cancer cells
The existence of a multiprotein complex containing UBXN2A, CHIP, and mot‐2 suggests a synergistic tumor suppressor activity of UBxN 2A and CHIP in mot‐ 2‐enriched tumors, and validates the UB XN2a‐CHIP axis as a novel and potential therapeutic target in CRC. Expand
DAB2IP inhibits p53 ubiquitin-mediated degradation by competitively binding to GRP75 and suppresses tumor malignancy in colon cancer
A novel function of DAB2IP is demonstrated to up-regulate the stability of wild-type TP53 by inhibiting its degradation in a ubiquitin-proteasome-dependent manner and provides a novel molecular aspect of the p53 pathway. Expand
UBXD Proteins: A Family of Proteins with Diverse Functions in Cancer
  • K. Rezvani
  • Biology, Medicine
  • International journal of molecular sciences
  • 2016
This review covers recent advances that elucidate the therapeutic potential of selected members of the UBXD family that can contribute to tumor growth. Expand
GRP75 modulates oncogenic Dbl-driven endocytosis derailed via the CHIP-mediated ubiquitin degradation pathway
It is shown for the first time that proto-Dbl (dbl proto-oncogene product) is co-enriched with mitochondrial chaperone GRP75 in endocytosis vesicles from ovarian cancer cells. Expand
Essential Roles of E3 Ubiquitin Ligases in p53 Regulation
  • S. Sane, K. Rezvani
  • Chemistry, Medicine
  • International journal of molecular sciences
  • 2017
This review provides a comprehensive understanding of p53 regulation by selective E3 ubiquitin ligases and their potential to be considered as a new class of biomarkers and therapeutic targets in diverse types of cancers. Expand
Therapeutic potency of heat-shock protein-70 in the pathogenesis of colorectal cancer: current status and perspectives.
This review summarizes the different tumorigenic properties of H SP70 and the potential therapeutic potency of HSP70 inhibitors in terms of a novel strategy for colorectal cancer therapy, for a better understanding, and hence better management of this disease. Expand
Heat Shock Protein 70 and Cancer
In this chapter, the roles of HSP70s in cancer biology and pharmacology are thoroughly discussed and important functions in the molecular mechanisms leading to cancer development, progression, and metastasis are discussed. Expand
Heat Shock Proteins and Cancer.
The roles of major HSPs in cancer biology and pharmacology are reviewed to comprehensively review the role they play in the molecular mechanisms leading to cancer development and metastasis. Expand


Ubiquitin-like (UBX)-domain-containing protein, UBXN2A, promotes cell death by interfering with the p53-Mortalin interactions in colon cancer cells
UBXN2A is introduced as a home defense response protein, which can reconstitute inactive p53-dependent apoptotic pathways and inhibit the binding between mot-2 and p53, which is an attractive therapeutic strategy in mot- 2-elevated tumors. Expand
Withanone binds to mortalin and abrogates mortalin-p53 complex: computational and experimental evidence.
A molecular interaction basis that could be used for screening and development of anticancer drugs with low toxicity to normal cells is established and accurate knowledge of the 3D structure of mortalin would further enhance the potential of such analyses to understand the molecular basis ofmortalin biology and mortalin based cancer therapy. Expand
Identifications small molecules inhibitor of p53-mortalin complex for cancer drug using virtual screening
Three drug-like compounds are identified adequate to interrupt stability of p53-mortalin complex that warrant for anticancer agent. Expand
Nucleocytoplasmic Translocation of UBXN2A Is Required for Apoptosis during DNA Damage Stresses in Colon Cancer Cells
It is shown that nucleocytoplasmic translocation of UBXN2A in response to stresses is necessary for its anti-cancer function in the cy toplasm, as well as activation of other mot-2-dependent growth promoting pathways. Expand
UBXN2A regulates nicotinic receptor degradation by modulating the E3 ligase activity of CHIP.
UBXN2A interferes with CHIP-mediated ubiquitination of α3 and protects the nicotinic receptor subunit from endoplasmic reticulum associated degradation (ERAD). Expand
UBXD4, a UBX-Containing Protein, Regulates the Cell Surface Number and Stability of α3-Containing Nicotinic Acetylcholine Receptors
The data suggest that UBXD4 modulates the distribution of α3* nAChRs between specialized intracellular compartments and the plasma membrane by controlling the stability of the α3 subunit and, consequently, the number of receptors at the cell surface. Expand
Identification and Functional Characterization of Nuclear Mortalin in Human Carcinogenesis*
It is demonstrated that mot-N promotes carcinogenesis and cancer cell metastasis by inactivation of tumor suppressor protein p53 functions and by interaction and functional activation of telomerase and heterogeneous ribonucleoprotein K (hnRNP-K) proteins. Expand
Activation of Wild Type p53 Function by Its Mortalin-binding, Cytoplasmically Localizing Carboxyl Terminus Peptides*
Cytoplasmically localizing p53 peptides harboring the residues 323-337 activated the endogenous p53 function by displacing it from p53-mortalin complexes and relocating it to the nucleus, sufficient to cause growth arrest of human osteosarcoma and breast carcinoma cells. Expand
Mortalin–p53 interaction in cancer cells is stress dependent and constitutes a selective target for cancer therapy
It is demonstrated that the mortalin–p53 interaction exists in cancer cells that are either physiologically stressed (frequently associated with p53 mutations) or treated with stress-inducing chemicals. Expand
The Chaperone-associated Ubiquitin Ligase CHIP Is Able to Target p53 for Proteasomal Degradation*
It is shown that the chaperone-associated ubiquitin ligase CHIP is able to induce the proteasomal degradation of p53, and that mutant and wild-type p53 transiently associate with molecular chaperones and can be diverted onto a degradation pathway through this association. Expand