The Prohormone ‘Proopiomelanocortin’ (POMC) is involved in several important cell functions. Critically review this statement in terms of its involvement in human pigmentation.

A dissertation presented by

Rekha Balakrishnan

For the BSc (Hons) in Biomedical Sciences

In the

University of Bradford

Division of Biomedical Sciences

School of Life Sciences

University of Bradford

Bradford

DATE of SUBMISSION

3rd April 2009

WORD COUNT

4788

TABLE OF CONTENTS

The Importance of POMC- derived Peptide............................................... 15

7

POMC and Pathology        

Conclusion        22

Abstract

This work reviews several important cellular-based functions of proopiomelanocortin (POMC), with emphasis on human skin pigmentation. As melanocortin peptides, PMOC regulates several physiological functions, including skin pigmentation, adrenal and cardiovascular functions, inflammation, energy homeostasis, and exocrine secretion. It also produces an array of biologically active peptides, by means of an extensive, tissue-specific posttranslational process. The skin is a target organ for the actions of POMC and its derived neuropeptides, including α-melanocyte stimulating hormone (α-MCH), β-endorphin, and ACTH.

This study also surveys diseases associated with POMC gene mutations. These defects lead to complex medical ailments, including deficiency in corticotropin, severe, early-onset obesity, and hypopigmentation. In the same vein, POMC and its derived neuropeptides are necessary components of several nervous system and body tissue processes.

The site of production and manner of delivery determine the way, in which POMC derived peptides act. These peptides behave as cytokines, growth factors, neurotransmitters and hormones. In the cutaneous cells, POMC peptides affect melanin pigmentation, immune activity and migratory capabilities Consequently, it has been conjectured that the skin POMC system plays a significant role in preserving the integrity of the skin, thereby reducing disturbances to internal metabolic equilibrium.    

Introduction

The POMC gene engenders the encoding of a polypeptide hormone precursor. The latter utilises prohormone convertases, in order to exhibit widespread post translational processing. The POMC undergoes cleavage during such processing. The peptides derived from it affect among other things, pain, energy homeostasis and modulation of immunity (proopiomelanocortin, 2009). In short, the compound is both created in and affects the function of the skin.

The skin is a repository for the complete system required for POMC processing (Mazurkiewicza, Corliss, & Slominski, July 2000). The result of interaction between opiate receptors, MC1R, MC2R, MC5R and POMC peptides is control of adnexal functions, keratinocytes and fibroblast activity, proliferation and secretory responses, and pigmentation of the hair and skin (Arck, Slominski, Theoharis, Peters, & Paus, August 2006).

         The neuroendocrine protein proopiomelanocortin (POMC) and its derivative neuropeptides play an important role in several control-oriented processes: the local activation of melanocortin or MC receptors, extracellular proteolytic processing (König, Luger, & Schol, 31 Jul 2006, P 751-761), and the bio-availability of adrenocorticotropin and associated hormones that stimulate melanocyte in the skin. In the latter, cutaneous melanocortin receptors are controlled by peptides like neprilysin or neutral endopeptidase (NEP) and that of ACE or angiotensin (a converting enzyme) (König, Luger, & Schol, 31 Jul 2006, P 751-761).

          Teofoli et al., found that POMC originates in the pituitary. Subsequently, its expression was discovered in epidermal keratinocytes, macrophages and melanocytes (Teofoli, Motoki, Lotti, Uitto, & Mauviel, April 2006). Following this study, Rousseau et al., found that ACTH and melanocortin peptides may be obtained from POMC processing; however, POMC processing was not completed in all observed cells. As such, the study found POMC release from skin cells to be a major controlling-factor in ACTH and melanocortin production (Rousseau, et al., June 2007).

In some cell cultures, the addition of melanocortins failed to increase melanocyte pigmentation. However, some research studies noted that some melanocyte cultures, is substantially affected by α – MSH. Therefore, local control proved to have greater relevance than circulating levels (Rees, 2003, P 76).

Slominski et al., emphasised that the skin is a target organ for the actions of POMC and its derived neuropeptides. These peptides include α-melanocyte stimulating hormone or α-MCH, β-endorphin and ACTH. Skin expression levels of POMC genes and corticotrophin releasing hormone peptides or CRH peptides are not variable (Slominski A. , Wortsman, Luger, Paus, & Solomon, July 2000, PP. 979-1020 ). Their levels are assessed by observing several factors that include: the physiological changes related to hair cycles, which are greater during the anagen phase; physiological changes due to UVR exposure; immune cytokine release; or the presence of cutaneous pathology. The pro-inflammatory interleukin-1 is a major factor that influences the cutaneous levels of the peptides including POMC, mRNA and MSH receptors. The skin expression of the CRH or POMC systems is stimulated by ultraviolet radiation (UVR). It also stimulates the expression of the corresponding receptors (Slominski, Wortsman, Luger, Paus, & Solomon, July 2000, PP. 979-1020 ).

The POMC gene engenders the encoding of a polypeptide hormone precursor. The latter utilises prohormone convertases, in order to exhibit widespread post-translational processing. The POMC undergoes cleavage during such processing, where the  peptides derived from it affect, among other things, pain, energy homeostasis, and the modulation of immunity (proopiomelanocortin, 2009).

In 2005, Millington described the cutaneous roles of POMC. Synthesis of the messenger RNA or mRNA associated with POMC transpires in the brain, pituitary, and the skin. When mRNA reaches the secretory granules, enzymatic alterations result in peptides, which on cleavage yield a number of products like α-MSH. It is theoretically possible for skin pigmentation modification to take place if there is a mutation in any of these cleavage processes. For instance, the outcomes of POMC and PC1 mutations result in pale skin, red hair, early-onset obesity, and adrenal failure (Millington, 2006).

The corticotropin releasing-factor is an expression of POMC in the skin as well as the production of POMC peptides. Proceeding its expression, the skin processes the final POMC peptides, including α-MSH, β-endorphin, ACTH, and β-LPH. Slominski  et al. cultured these peptides and POMC precursors in hair follicles and cutaneous cells and tissue (Slominski, Wortsman, Luger, Paus, & Solomon, July 2000, PP. 979-1020 ) in order to show the variety of skin-related repositories that facilitate POMC processing (Mazurkiewicza, Corliss, & Slominski, July 2000). The result of interaction between opiate receptors, MC1R, MC2R, MC5R and POMC peptides is control of adnexal functions, keratinocytes and fibroblast activity, proliferation and secretory responses, and pigmentation of the hair and skin (Arck, Slominski, Theoharis, Peters, & Paus, August 2006).

Cell Functions of POMC

Melanocortin peptides regulate several physiological functions. These peptides regulate skin pigmentation, adrenal functions, cardiovascular functions and control, inflammation, energy homeostasis, and exocrine secretion. These receptors belong to the family of G protein-coupled receptors (GPCR). In general, a response is regarded as melanocortin-receptor binding (Roberts, Newton, Beaumont, Leonard, & Sturm, 2005, P 76). The chief functions of skin cell peptides are chiefly focused on: melanin pigmentation; immune activity; immunosuppression; functions pertaining to eccrine glands, hair follicles and sebaceous glands; and secretory activities and proliferation (Slominski, 2005). It also contains melanocortin systems that respond to both internal and external stress (which is countered through several mechanisms, including local pigmentation of the skin, immune structures, epidermal mechanisms, and the adnexal and vascular systems). Skin function is thus stabilized through these responses to stress factors. Ultimately, these peptides prevent disorders of, and interruptions to, internal homeostasis (Tsatmali, Ancans, & Thody, 2002).

POMC is also associated with several types of inflammatory skin disorders, prompted by melanocortin levels. Additionally, research has shown that POMC genes and marginal physical attributes (such as the red hair phenotype) are closely associated (Bastiaens, Huurne, Kielich, Gruis, Westendorp, & Vermeer, 2001). For example, children whose POMC gene had been rendered inactive due to mutations, have been observed to be afflicted with a pleiotropic syndrome that encompasses changes to the pigmentation of the hair and skin, severe obesity, and secondary hypocortisolism (Clement, et al., December 2008). In the absence of ligands derived from POMC, other genetic variants become active and ensure that eumelanin synthesis is maintained; this is with respect to ethnic groups whose members are mainly dark haired.  However, this is not the case with ethnic groups from Northern European countries, wherein eumelanin synthesis is chiefly dependant on POMC-derived ligands (Farooqi & O'Rahilly, 2006, P 713). The research work of Farooqi, O’Rahilly, and others has shown that the deficiency of POMC generally results in isolated ACTH deficiency, hyperphagia, and early-onset obesity. Red hair is a fundamental indication of POMC deficiency in patients of the Caucasian race. However, this feature does not typically provide a diagnostic clue to determine the deficiency of POMC in other races (Farooqi & O'Rahilly, 2006, P 713).

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Several skin diseases are caused by POMC peptides. Research studies indicate that skin diseases like severe atopic dermatitis, psoriasis, scarring alopecia, and inflammatory keloids are on account of the abnormal expression of these peptides. It was also established that nodular-type, metastatic melanomas and basal cell carcinoma occur due to abnormal expressions of POMC peptides (Slomanski, Wortsman, Mazurkiewicz, Matsuoka, Dietrich, & Lawrence, 1993).

Alaluf et al. showed that variation in skin pigmentation is chiefly on account of biological pigments in the skin tissues, though there are several other factors that can regulate the process of melanogenesis in the melanocyte – namely, ...

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