Human Metallothionein Expression under Normal and Pathological Conditions: Mechanisms of Gene Regulation Based on In silico Promoter Analysis

Abstract

Metallothioneins (MTs) are ubiquitous metal-binding proteins that have been highly conserved throughout evolution. Although their physiological function is not completely understood, they are involved in diverse processes including metal homeostasis and detoxification, the oxidative stress response, inflammation, and cell proliferation. Te human MT gene family consists of at least 18 isoforms, containing pseudogenes as well as genes encoding functional proteins. Most of the MT isoforms can be induced by a wide variety of substances, such as metals, cytokines, and hormones. Different cell types express discrete MT isoforms, which reflects the specifically adapted functions of MTs and a divergence in their regulation. Te aberrant expression of MTs has been described in a number of diseases, including Crohn's disease, cancer, Alzheimer's disease, amyotrophic lateral sclerosis, Menkes disease, and Wilson's disease. Therefore, a thorough understanding of MT gene regulation is imperative. To date, the transcriptional regulation of MTs has primarily been studied in mice. While only four murine MT isoforms exist, the homology between murine and human MTs allows for the evaluation of the regulatory regions in their respective promoters. Here, we review the aberrant expression of MTs in human diseases and the mechanisms that regulate MT1 expression based on an in silico evaluation of transcription factor binding sites.

Metallothionein expression in colorectal cancer: relevance of different isoforms for tumor progression and patient survival

“…Nevertheless, what is not appreciated when assessing the tumor immunoreactivity of MT is that a family of genes (MT1A, MT1B, MT1E, MT1F, MT1G, MT1H, MT1M, MT1X, MT2A, MT3 and MT4) with MT1 and MT2 being expressed ubiquitously at low levels, MT3 in neurons, glia and male reproductive organs, and MT4 in differentiating stratified squamous epithelial cells [23]. Due to the high sequence homology of MT variants, commercially available antibodies are not able to discriminate between MT1 + 2 isoforms.…”

Evaluation ofalpha-methylacyl-CoA racemase, metallothionein and prostate specific antigen as prostate cancer prognostic markers

“…Moreover, this marker has been found elevated even in other types of cancers such as breast carcinoma [66], head and neck cancer [67], medulloblastoma [35], melanoma [68,69] and other [70][71][72][73][74]. Nevertheless, combination of MT and PSA levels could be of prognostic significance due to possible revealing of false positive results, but this assumption needs to be investigated in greater details.…”

Residue Modification and Mass Spectrometry for the Investigation of Structural and Metalation Properties of Metallothionein and Cysteine-Rich Proteins

“…Mammalian MTs have four main isoforms: MT-1 and MT-2 expressed constitutively with a higher content in liver and kidneys [23,24], MT-3 expressed mainly in the brain and central nervous system [25], and MT-4 expressed in cornified, stratified, squamous epithelium, a protective tissue found on many organs including the skin, tongue, and vagina [26]. The conserved sequences between the mammalian isoforms contain the 20 cysteines that are essential for metal binding, Figure 1.…”