Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.22 (cdc2)
 8,319 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Microphthalmia-associated transcription factor (Mitf) is essential for melanocyte development and function and regulates anti-apoptotic Bcl2 expression. We hypothesized that cellular deficiency of Mitf can influence melanocyte survival in response to ultraviolet (UV) radiation. Primary melanocyte cultures were prepared from neonatal wild-type mice and congenic animals heterozygous for Mitf mutations Mitf (mi-vga9/+) and Mitf(Mi-wh/+) and exposed to UV irradiation. Wild-type melanocytes were more resistant to UV-induced apoptosis than melanocytes partially deficient in Mitf activity, as determined by relative levels of intracellular melanin and relative activation of Mitf target genes Tyr, Tyrp1, Dct, and Cdk2. Comparative experiments with wild-type cells and congenic albino melanocytes demonstrated that these differences are not due to differences in melanin content, implicating Mitf as a primary determinant of UV-dependent melanocyte survival. Mitf activity correlated directly with resistance to UV-induced apoptosis in melanocytes. Mitf was important not only for regulating the expression of anti-apoptotic Bcl-2 following UV irradiation, but also the expression of the pro-apoptotic BH3-only Bad protein and activation of the extrinsic apoptotic pathway. Hence, Mitf is a multifaceted regulator of UV-induced apoptosis in melanocytes.
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PMID:Mitf dosage as a primary determinant of melanocyte survival after ultraviolet irradiation. 1919 12

In melanoma, as well as in other solid tumors, the cells within a given tumor exhibit strong morphological, functional and molecular heterogeneity that might reflect the existence of different cancer cell populations, among which are melanoma-initiating cells (MICs) with 'stemness' properties and their differentiated, fast-growing progeny. The existence of a slow-growing population might explain the resistance of melanoma to classical chemotherapies that target fast growing cells. Therefore, elucidating the biologic properties of MICs and, more importantly, the molecular mechanisms that drive the transition between MICs and their proliferating progeny needs to be addressed to develop an efficient melanoma therapy. Using B16 mouse melanoma cells and syngeneic mice, we show that the inhibition of microphthalmia-associated transcription factor (Mitf), the master regulator of melanocyte differentiation, increases the tumorigenic potential of melanoma cells and upregulates the stem cell markers Oct4 and Nanog. Notably, p27, the CDK inhibitor, is increased in Mitf-depleted cells and is required for exacerbation of the tumorigenic properties of melanoma cells. Further, a slow-growing population with low-Mitf level and high tumorigenic potential exists spontaneously in melanoma. Ablation of this population dramatically decreases tumor formation. Importantly, these data were confirmed using human melanoma cell lines and freshly isolated human melanoma cell from lymph node and skin melanoma metastasis. Taken together our data, identified Mitf and p27 as the key molecular switches that control the transition between MICs and their differentiated progeny. Eradication of low-Mitf cells might be an appealing strategy to cure melanoma.
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PMID:Mitf is the key molecular switch between mouse or human melanoma initiating cells and their differentiated progeny. 2127 92

Previous studies have reported that repeated solar and artificial UVB (280-320 nm) and UVA (320-400 nm) exposures can modify acquired melanocytic nevi (AMN). We therefore investigated the clinical, dermoscopic, histological and immunohistochemical changes in AMN exposed to UVB and UVA radiation. Twenty healthy volunteers with at least three AMN on the trunk were enrolled in the present study and randomized into two groups to receive equally effective doses of narrow-band (NB)-UVB or UVA1. Three exposures per week were delivered for a total of 4 weeks. During exposures, one AMN was left unprotected, a second one was shielded with an opaque adhesive tape and the third nevus was covered with a commercial sunscreen. After the irradiation cycle, the AMN were surgically removed and underwent histological and immunohistochemical assessment of melanocyte/melanogenesis-related proteins (MART-1, tyrosinase, HMB-45), cell cycle activation markers (Ki-67, topoisomerase IIalpha, p53, Cdk2) and transcription factors (microphthalmia-associated transcription factor, STAT3). Nevi that were exposed to NB-UVB or UVA1 also showed statistically significant increase in size and changes in their dermoscopic features, including overall darkening, increased pigment network expression, formation of branched streaks, and increased number and size of brown globules and dots. AMN that had been covered with opaque tape or sunscreen did not show changes in size or dermoscopic features following UVA1 or NB-UVB exposure. Histological and immunohistochemical analysis did not show any significant change in exposed AMN in comparison with AMN shielded with an opaque adhesive tape or covered with the sunscreen.
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PMID:Dermoscopic, histological and immunohistochemical evaluation of cancerous features in acquired melanocytic nevi that have been repeatedly exposed to UVA or UVB. 2210 32