Cutaneous melanin pigment plays a critical role in camouflage, mimicry, social communication, and protection against harmful effects of solar radiation. Melanogenesis is under complex regulatory control by multiple agents interacting via pathways activated by receptor-dependent and -independent mechanisms, in hormonal, auto-, para-, or intracrine fashion. Because of the multidirectional nature and heterogeneous character of the melanogenesis modifying agents, its controlling factors are not organized into simple linear sequences, but they interphase instead in a multidimensional network, with extensive functional overlapping with connections arranged both in series and in parallel. The most important positive regulator of melanogenesis is the MC1 receptor with its ligands melanocortins and ACTH, whereas among the negative regulators agouti protein stands out, determining intensity of melanogenesis and also the type of melanin synthesized. Within the context of the skin as a stress organ, melanogenic activity serves as a unique molecular sensor and transducer of noxious signals and as regulator of local homeostasis. In keeping with these multiple roles, melanogenesis is controlled by a highly structured system, active since early embryogenesis and capable of superselective functional regulation that may reach down to the cellular level represented by single melanocytes. Indeed, the significance of melanogenesis extends beyond the mere assignment of a color trait.

https://www.physiology.org/doi/pdf/10.1152/physrev.00044.2003

Melanin Pigmentation in Mammalian Skin and Its Hormonal Regulation

S100: a multigenic family of calcium-modulated proteins of the EF-hand type with intracellular and extracellular functional roles.

The efficacy of endocrine therapies (such as tamoxifen) in breast cancer is limited by intrinsic and acquired therapeutic resistance. What do we know about the genetic lesions and molecular processes that determine endocrine resistance in the clinic, and how can we use this to improve therapy? Endocrine therapies targeting oestrogen action (anti-oestrogens, such as tamoxifen, and aromatase inhibitors) decrease mortality from breast cancer, but their efficacy is limited by intrinsic and acquired therapeutic resistance. Candidate molecular biomarkers and gene expression signatures of tamoxifen response emphasize the importance of deregulation of proliferation and survival signalling in endocrine resistance. However, definition of the specific genetic lesions and molecular processes that determine clinical endocrine resistance is incomplete. The development of large-scale computational and genetic approaches offers the promise of identifying the mediators of endocrine resistance that may be exploited as potential therapeutic targets and biomarkers of response in the clinic.

Biological determinants of endocrine resistance in breast cancer

This article reviews the mechanisms of bacterial adhesion to biomaterial surfaces and the factors affecting the adhesion The process of bacterial adhesion includes an initial physicochemical interaction phase (phase one) and a late molecular and cellular interaction phase (phase two), which is a complicated process affected by many factors, including the characteristics of the bacteria themselves, the target material surface, and the environmental factors, such as the presence of serum proteins or bactericidal substances

Concise review of mechanisms of bacterial adhesion to biomaterial surfaces.

We performed subtractive and differential hybridization for transcript comparison between murine fibroblasts and isogenic epithelium, and observed only a few novel intracellular genes which were relatively specific for fibroblasts. One such gene encodes a filament-associated, calcium-binding protein, fibroblast-specific protein 1 (FSP1). The promoter/enhancer region driving this gene is active in fibroblasts but not in epithelium, mesangial cells or embryonic endoderm. During development, FSP1 is first detected by in situ hybridization after day 8.5 as a postgastrulation event, and is associated with cells of mesenchymal origin or of fibroblastic phenotype. Polyclonal antiserum raised to recombinant FSP1 protein stained the cytoplasm of fibroblasts, but not epithelium. Only occasional cells stain with specific anti-FSP1 antibodies in normal parenchymal tissue. However, in kidneys fibrosing from persistent inflammation, many fibroblasts could be identified in interstitial sites of collagen deposition and also in tubular epithelium adjacent to the inflammatory process. This pattern of anti-FSP1 staining during tissue fibrosis suggests, as a hypothesis, that fibroblasts in some cases arise, as needed, from the local conversion of epithelium. Consistent with this notion that FSP1 may be involved in the transition from epithelium to fibroblasts are experiments in which the in vitro overexpression of FSP1 cDNA in tubular epithelium is accompanied by conversion to a mesenchymal phenotype, as characterized by a more stellate and elongated fibroblast-like appearance, a reduction in cytokeratin, and new expression of vimentin. Similarly, tubular epithelium submerged in type I collagen gels exhibited the conversion to a fibroblast phenotype which includes de novo expression of FSP1 and vimentin. Use of the FSP1 marker, therefore, should further facilitate both the in vivo studies of fibrogenesis and the mapping of cell fate among fibroblasts.

https://rupress.org/jcb/article-pdf/130/2/393/1264768/393.pdf

Identification and characterization of a fibroblast marker: FSP1.

Epidermal-growth-factor receptors and oestrogen receptors in human breast cancer.

Resveratrol-induced apoptosis in human T-cell acute lymphoblastic leukaemia MOLT-4 cells.

The S100 family of calcium binding proteins has been shown to be involved in a variety of physiological function, such as cell proliferation, extracellular signal transduction, intercellular adhesion, motility as well as cancer metastasis. The role played by a member of the S100 gene family, viz. S100A4 (also referred to as mtsl, 18A2/mtsl, pEL-98, p9Ka, metastasin) in the control of cell proliferation as well as in cancer invasion and metastasis has now been extensively studied in a number of laboratories. The protein encoded by S100A4 gene is now known to be capable of regulating cell cycle progression, modulating intercellular adhesion and invasive and metastatic properties of cancer cells. The S100A4 protein appears to be able to sequester and disable the p53 suppressor protein which controls G1-S transition of cells as well as the exit of cells from the S phase into mitosis G2-M transition is believed to involve the induction of stathmin (Op18) gene expression. The expression of this gene has been found to parallel that of S100A4, S100A4 also appears to take part in the homeostasis of growth, with apparent involvement also in growth factor signal transduction and apoptotic cell death. There is considerable evidence that S100A4 expression alters the adhesive properties of cells, possibly by remodelling the extracellular matrix and promoting a redeployment of adhesion-mediating macromolecules occurring in the extracellular matrix. Using transfection technology, it has been shown that over-expression of S100A4 enhances lung colonisation by cancer cells. The transfection and expression of antisense constructs, in contrast, inhibit metastatic localisation in the lung. S100 proteins levels in serum and in tumour tissue are increasingly being monitored and have been regarded as good indicators of the state of cancer progression. Valuable evidence has accumulated regarding the expression of S100A4 in human melanomas. In carcinoma of the breast, the level of expression of S100A4 has been found to be closely related to metastatic spread of the cancer to regional lymph nodes. The purpose of this review is to emphasise the need to focus sharply upon the mechanisms by which S100 proteins in general and S100A4 in particular subserve the wide variety of functions currently attributable to them.

S100A4 (MTS1) calcium binding protein in cancer growth, invasion and metastasis.

Metastasis promoter S100A4 is a potentially valuable molecular target for cancer therapy.

The nm23 and mts1 genes are associated with the expression of the metastatic phenotype. We have shown previously that modulation of metastatic behaviour produces parallel changes in the expression of these genes and that the expression of the two genes is co-regulated. Here we show that modulation of gene expression affects the process of tubulin polymerisation. B16 melanoma cell lines F1 and ML8 were treated with alpha melanocyte stimulating hormone (MSH) and all-trans retinoic acid (RA) respectively. MSH reduced the proportion of nm23+ and increased mts1+ F1 cells, with a 55% decrease in the ratio nm23:mts1. In parallel, MSH increased the expression of depolymerised form of tubulin in these cells. Treatment of ML8 cells with RA decreased mts1 positivity to a greater extent that nm23 positivity and the nm23:mts1 ratio increased by 70% and, in parallel, reduced the expression of depolymerised form of tubulin. These data suggest that nm23 and mts1 gene expression regulates the biological behaviour of the tumour cell and confer on it invasive and metastasizing properties by affecting the state of tubulin polymerisation.

Metastasis associated MTS1 and NM23 genes affect tubulin polymerisation in B16 melanomas: a possible mechanism of their regulation of metastatic behaviour of tumours.

Gajanan V. Sherbet

Papers

Epidermal-growth-factor receptors and oestrogen receptors in human breast cancer.

Resveratrol-induced apoptosis in human T-cell acute lymphoblastic leukaemia MOLT-4 cells.

S100A4 (MTS1) calcium binding protein in cancer growth, invasion and metastasis.

Metastasis promoter S100A4 is a potentially valuable molecular target for cancer therapy.

Metastasis associated MTS1 and NM23 genes affect tubulin polymerisation in B16 melanomas: a possible mechanism of their regulation of metastatic behaviour of tumours.