Cancer

FSH R, or follicle-stimulating hormone receptor, is a transmembrane G-protein coupled receptor that is expressed in the ovaries, uterus, and testes. The ligand for this receptor, considered to be the central hormone of mammalian reproduction, is called follicle stimulating hormone (FSH) [1]. In females, FSH R is essential for proper ovarian development and follicle maturation. In males, it is required for normal spermatogenesis.

ChREBP (carbohydrate response element-binding protein) is a glucose responsive basic helix-loop-helix/leucine zipper (bHLH/LZ) transcription factor that binds MLX and then carbohydrate response element /ChoRE for the induction of genes involved in glycolysis, de novo lipogenesis (DNL), and fatty acid desaturation. ChREBP’s target genes includes glucokinase (GCK), fatty acid synthase (FAS), acetyl-CoA carboxylase (ACC), pyruvate kinase/liver type pyruvate kinase (PK1/ PKLR), delta-9-desaturase (SCD/SCD1) etc.

Copper is an essential micronutrient that serves as a cofactor in numerous biological processes, but can be toxic when present in excess. Because of this, cells must tightly maintain copper levels. This includes balance between import and export of cellular copper. The major copper importer in humans is the high-affinity copper transporter SLC31A1 or CTR1. The localization of CTR1 varies between cell types, but is commonly found at the plasma membrane and intracellular vesicles [1-3].   

The c-Jun N-terminal kinase (JNK) family is a group of regulatory kinases with important functions in cell morphogenesis, inflammation, differentiation, and cell death (1). Aberrant activation of JNK family proteins in cancers has led to interest in small molecule JNK inhibitors as a therapeutic strategy (1). JNK1, also known as MAPK8, is expressed in most tissues and is involved in transduction of extracellular signals such as growth factors or cytokines though a phosphorylation cascade to elicit diverse intracellular responses (1).

The inflammatory response consists of a complex network of signaling pathways that regulate a diverse set of cytokines, growth factors, adhesion molecules, and transcription factors (1). Of the proinflammatory signaling pathways the NF-kB family is particularly well studied for its role in apoptosis, cancer, and the development and maintenance of the immune system (1). The family consists of the transcription factors p50, p52, RelA (p65), RelB, and c-Rel.

Mitogen-activated protein kinases (MAPKs) are important signaling proteins needed to transmit and relay extracellular stimuli and to illicit intracellular responses (1). The MAPK family of proteins are serine/threonine kinases that are able to phosphorylate and activate downstream kinases in a signal cascade that regulates diverse cell responses such as gene expression, metabolism, apoptosis, and differentiation (1). Notable members of the MAPK family include ERK, JNK, and p38 (1).

Thyroid transcription factor 1 (TTF-1), also known as NKX2.1, is a conserved master regulatory transcription factor involved in the development of the lung, brain, and thyroid (1). In the lung TTF-1 positively regulates the expression of several lung-specific proteins including thyroglobulin, thyroperoxidase, and surfactant proteins A, B, and C (1).

AKT1 is a serine/threonine protein kinase with homology to protein kinase A (PKA) and protein kinase C (PKC). AKT1 contains the central kinase domain sandwiched between a pleckstrin homology domain and a regulatory domain (1). AKT1 is regulated by receptor tyrosine kinase pathways and is activated in a PI3K-dependent manner following growth factor stimulation (1).

p53 is a tumor suppressor that has a central role in regulating cell cycle arrest, DNA repair, and apoptosis. p53 is widely studied for its role in cancer and is mutated or altered in more than half of all cancers (1). This widespread role in tumorigenesis has made p53 one of the most highly studied proteins and a target for anti-cancer therapeutics. Normally, p53 allows cells to sense and respond to cellular stress such as DNA damage or hypoxia (2). In response to these signals, p53 is activated through post-translational modification and protein stabilization.

The aryl hydrocarbon receptor (AHR) is a ligand activated transcription factor that controls the expression of a diverse set of genes. In the absence of ligand, AHR is retained in the cytoplasm. Upon ligand binding AHR translocates to the nucleus where it forms a heterodimer with aryl hydrocarbon receptor nuclear translocator (ARNT) (1). This receptor complex then recognizes AHR-response elements in target genes to regulate their transcription.