In the past fifteen years, it has become apparent that tumour-associated p53 mutations can provoke activities that are different to those resulting from simply loss of wild-type tumour-suppressing p53 function. Many of these mutant p53 proteins acquire oncogenic properties that enable them to promote invasion, metastasis, proliferation and cell survival. Here we highlight some of the emerging molecular mechanisms through which mutant p53 proteins can exert these oncogenic functions.

p53 mutations in cancer

Genetic and biochemical studies in lower eukaryotes have identified several proteins that ensure accurate segregation of chromosomes. These include the Drosophila aurora and yeast Ipl1 kinases that are required for centrosome maturation and chromosome segregation. We have identified two human homologues of these genes, termed aurora1 and aurora2, that encode cell-cycle-regulated serine/threonine kinases. Here we demonstrate that the aurora2 gene maps to chromosome 20q13, a region amplified in a variety of human cancers, including a significant number of colorectal malignancies. We propose that aurora2 may be a target of this amplicon since its DNA is amplified and its RNA overexpressed, in more than 50% of primary colorectal cancers. Furthermore, overexpression of aurora2 transforms rodent fibroblasts. These observations implicate aurora2 as a potential oncogene in many colon, breast and other solid tumors, and identify centrosome-associated proteins as novel targets for cancer therapy.

A homologue of Drosophila aurora kinase is oncogenic and amplified in human colorectal cancers

https://www.cell.com/cancer-cell/pdf/S1535-6108(14)00037-3.pdf

Mutant p53 in Cancer: New Functions and Therapeutic Opportunities

http://www.thehealersbible.com/uploads/1/2/9/0/12907633/biological_activities_of_curcumin.pdf

Biological activities of curcumin and its analogues (Congeners) made by man and Mother Nature.

Clinical resistance is a complex phenomenon in major human cancers involving multifactorial mechanisms, and hypoxia is one of the key components that affect the cellular expression program and lead to therapy resistance. The present study aimed to summarize the role of hypoxia in cancer therapy by regulating the tumor microenvironment (TME) and to highlight the potential of hypoxia-targeted therapy. Relevant published studies were retrieved from PubMed, Web of Science, and Embase using keywords such as hypoxia, cancer therapy, resistance, TME, cancer, apoptosis, DNA damage, autophagy, p53, and other similar terms. Recent studies have shown that hypoxia is associated with poor prognosis in patients by regulating the TME. It confers resistance to conventional therapies through a number of signaling pathways in apoptosis, autophagy, DNA damage, mitochondrial activity, p53, and drug efflux. Hypoxia targeting might be relevant to overcome hypoxia-associated resistance in cancer treatment.

/pdf/role-of-hypoxia-in-cancer-therapy-by-regulating-the-tumor-1gwkyv9xo8.pdf

Role of hypoxia in cancer therapy by regulating the tumor microenvironment

Esha Madan 1,2 , Rajan Gogna 2 , Madan Bhatt 3 , Uttam Pati 2 , Periannan Kuppusamy 4 , Abbas Ali Mahdi 1 1 Department of Biochemistry, Chhatrapati Shahuji Maharaj Medical University, Lucknow, India 2 Transcription and Human Biology Laboratory, School of Biotechnology, Jawaharlal Nehru University, New-Delhi, India 3 Department of Radiotherapy and Chemotherapy, Chhatrapati Shahuji Maharaj Medical University, Lucknow, India 4 Dorothy M Davis Heart and Lung Research institute, Department of Internal Medicine, Ohio State University, Columbus, Ohio, USA Received: December 19, 2011; Accepted: December 20, 2011; Published: December 31, 2011; Keywords: p53, Metabolism, TIGAR, SCO2, Tumor Suppressor Correspondence: Abbas Ali Mahdi, email: // // Abstract p53 is well known as the "guardian of the genome" for differentiated and neoplastic cells. p53 induces cell-cycle arrest and cell death after DNA damage and thus contributes to the maintenance of genomic stability. In addition to this tumor suppressor function for pro-oncogenic cells, p53 also plays an important role as the central regulator of stress response by maintaining cellular homeostasis at the molecular and biochemical level. p53 regulates aerobic respiration at the glycolytic and oxidative phosphorylation (OXPHOS) steps via transcriptional regulation of its downstream genes TP53-induced glycolysis regulator (TIGAR) and synthesis of cytochrome c oxidase (SCO2). p53 negatively regulates glycolysis through activation of TIGAR (an inhibitor of the fructose-2,6-bisphosphate). On the contrary p53 positively regulates OXPHOS through upregulation of SCO2, a member of the COX-2 assembly involved in the electron-transport chain. It is interesting to notice that p53 antagonistically regulates the inter-dependent glycolytic and OXPHOS cycles. It is important to understand whether the p53-mediated transcriptional regulation of TIGAR and SCO2 is temporally segregated in cancer cells and what is the relation between these paradoxical regulations of glycolytic pathway with the tumor suppressor activity of p53. In this review we will elucidate the importance of p53-mediated regulation of glycolysis and OXPHOS and its relation with the tumor suppressor function of p53. Further since cellular metabolism shares great relation with the process of aging we will also try and establish the role of p53 in regulation of aging via its transcriptional control of cellular metabolism.

/pdf/regulation-of-glucose-metabolism-by-p53-emerging-new-roles-1st0size48.pdf

Regulation of glucose metabolism by p53: Emerging new roles for the tumor suppressor

Design, synthesis and characterization of some bioactive conjugates of curcumin with glycine, glutamic acid, valine and demethylenated piperic acid and study of their antimicrobial and antiproliferative properties

Paraoxonase gene polymorphism and coronary artery disease in Indian subjects

CHIP chaperones wild type p53 tumor suppressor protein.

p53 induces cell-cycle arrest and apoptosis in cancer cells and negatively regulates glycolysis via TIGAR. Glycolysis is crucial for cancer progression although TIGAR provides protection from reactive oxygen species and apoptosis. The relation between TIGAR-mediated inhibition of glycolysis and p53 tumour-suppressor activity is unknown. RT–PCR, western blot, luciferase and chromatin immunoprecipitation assays were used to study TIGAR gene regulation. Co-IPP was used to determine the role of TIGAR protein in regulating the protein–protein interaction between retinoblastoma (RB) and E2F1. MCF-7 tumour xenografts were utilised to study the role of TIGAR in tumour regression. Our study shows that TIGAR promotes p21-independent, p53-mediated G1-phase arrest in cancer cells. p53 activates the TIGAR promoter only in cells exposed to repairable doses of stress. TIGAR regulates the expression of genes involved in cell-cycle progression; suppresses synthesis of CDK-2, CDK-4, CDK-6, Cyclin D, Cyclin E and promotes de-phosphorylation of RB protein. RB de-phosphorylation stabilises the complex between RB and E2F1 thus inhibiting the entry of cell cycle from G1 phase to S phase. TIGAR mediates de-phosphorylation of RB and stabilisation of RB–E2F1 complex thus delaying the entry of cells in S phase of the cell cycle. Thus, TIGAR inhibits proliferation of cancer cells and increases drug-mediated tumour regression by promoting p53-mediated cell-cycle arrest.

/pdf/tigar-induces-p53-mediated-cell-cycle-arrest-by-regulation-430is74t0c.pdf

Uttam Pati

Papers

Regulation of glucose metabolism by p53: Emerging new roles for the tumor suppressor

Design, synthesis and characterization of some bioactive conjugates of curcumin with glycine, glutamic acid, valine and demethylenated piperic acid and study of their antimicrobial and antiproliferative properties

Paraoxonase gene polymorphism and coronary artery disease in Indian subjects

CHIP chaperones wild type p53 tumor suppressor protein.

TIGAR induces p53-mediated cell-cycle arrest by regulation of RB–E2F1 complex