1p33

DD96,MAP17,SPAP

Cancer

Carcinomas of different origin, melanoma, etc.

Expression levels increase with stage in most carcinomas.

MAP17 (PDZK1IP1, DD96) enhances tumorigenic properties of melanoma cells through ROS increase (Guijarro et al., 2007b). Tumor cells that overexpress MAP17 show an increased tumoral phenotype with enhanced proliferative capabilities both in presence or absence of contact inhibition, decreased apoptotic sensitivity and increased migration. MAP17-expressing clones also grow better in nude mice. The increased malignant cell behavior induced by MAP17 are associated with an increase in ROS production, and the treatment of MAP17-expressing cells with antioxidants results in a reduction in the tumorigenic properties of these cells. Treatment of melanoma cells with inhibitors of Na⁺-coupled co-transporters lead to an inhibition of ROS increase and a decrease in the malignant cell behavior in MAP17-expressing clones. Finally, we show that MAP17-dependent ROS increase and tumorigenesis are dependent on its PDZ-binding domain, since disruption of its sequence by point mutations abolish its ability to enhance ROS production and tumorigenesis.
At the molecular level MAP17 protects Rat1a fibroblasts from Myc-induced apoptosis through ROS-mediated activation of the PI3K/AKT signalling pathway (Guijarro et al., 2007d). A fraction of PTEN undergoes oxidation in MAP17-overexpressing cells. Furthermore, activation of AKT by MAP17 as measured by Thr308 phosphorylation was independent of PI3K activity. Importantly, modulation of ROS by antioxidant treatment prevented activation of AKT, restoring the level of apoptosis in serum starved Rat1/c-Myc fibroblasts (Guijarro et al., 2007d).
MAP17 is overexpressed in a great variety of human carcinomas (Guijarro et al., 2007c). Immunohistochemical analysis of MAP17 during cancer progression shows in prostatic and ovarian carcinomas that overexpression of the protein strongly correlates with tumoral progression (Guijarro et al., 2007c).

Skin diseases

Abnormal keratinocyte differentiation.
In the meta-analysis of public microarray databases for different skin diseases, Noh and cols (Noh et al., 2010) revealed that MAP17 is commonly up-regulated suggesting that may be potentially associated with the abnormal keratinocyte differentiation. MAP17 was significantly up-regulated in response to interferon-gamma, interleukin 4 (IL-4), IL-6, IL-17A or IL-22 in normal human epidermal keratinocytes (NHEK). Interestingly, the PDZK1 gene is localized within the atopic dermatitis-linked region on human chromosome 1q21. In an attempt to evaluate whether MAP17 regulates the expression of cornified envelope-associated genes at the 1q21 locus, such as filaggrin, loricrin and involucrin, these authors found that the over-expression of MAP17 in HaCaT keratinocytes significantly decreased the expression of filaggrin, a cornified envelope-associated gene. Taken together, the Th cell cytokine-induced up-regulation of MAP17 expression may be linked to the down-regulation of filaggrin, which may be associated with the abnormal epidermal differentiation observed in the dermatological diseases (Noh et al., 2010).

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