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Biomedical subjects

Faith M Strickland

Publications and source records attributed to Faith M Strickland.

7 recordsLinked to original sources
PubMed2006

Calmodulin-androgen receptor (AR) interaction: calcium-dependent, calpain-mediated breakdown of AR in LNCaP prostate cancer cells.

Chemotherapy of prostate cancer targets androgen receptor (AR) by androgen ablation or antiandrogens, but unfortunately, it is not curative. Our attack on prostate cancer envisions the proteolytic elimination of AR, which requires a fuller understanding of AR turnover. We showed previously that calmodulin (CaM) binds to AR with important consequences for AR stability and function. To examine the involvement of Ca(2+)/CaM in the proteolytic breakdown of AR, we analyzed LNCaP cell extracts that bind to a CaM affinity column for the presence of low molecular weight forms of AR (intact AR size, approximately 114 kDa). Using an antibody directed against the NH(2)-terminal domain (ATD) of AR on Western blots, we identified approximately 76-kDa, approximately 50-kDa, and 34/31-kDa polypeptides in eluates of CaM affinity columns, suggesting the presence of CaM-binding sites within the 31/34-kDa ATD of AR. Under cell-free conditions in the presence of phenylmethylsulfonyl fluoride, AR underwent Ca(2+)-dependent degradation. AR degradation was inhibited by N-acetyl-leu-leu-norleu, an inhibitor of thiol proteases, suggesting the involvement of calpain. In intact cells, AR breakdown was accelerated by raising intracellular Ca(2+) using calcimycin, and increased AR breakdown was reversed with the cell-permeable Ca(2+) chelator bis-(O-aminophenoxy)-ethane-N,N,N',N'-tetraacetic acid tetra-(acetoxymethyl)-ester. In CaM affinity chromatography studies, the Ca(2+)-dependent protease calpain was bound to and eluted from the CaM-agarose column along with AR. Caspase-3, which plays a role in AR turnover under stress conditions, did not bind to the CaM column and was present in the proenzyme form. Similarly, AR immunoprecipitates prepared from whole-cell extracts of exponentially growing LNCaP cells contained both calpain and calpastatin. Nuclear levels of calpain and calpastatin (its endogenous inhibitor) changed in a reciprocal fashion as synchronized LNCaP cells progressed from G(1) to S phase. These reciprocal changes correlated with changes in AR level, which increased in late G(1) phase and decreased as S phase progressed. Taken together, these observations suggest potential involvement of AR-bound CaM in calcium-controlled, calpain-mediated breakdown of AR in prostate cancer cells.

Androgen Antagonists↗
PubMed2006

Dopachrome tautomerase (Dct) regulates neural progenitor cell proliferation.

DOPAchrome tautomerase (Dct) functions downstream of tyrosinase in the biosynthetic pathway of eumelanin by catalyzing the conversion of dopachrome to 5,5-dihydroxyindole-2-carboxylic acid (DHICA) in pigment cells. Dct transcription is regulated directly or synergistically by Pax3, Sox10 and microphthalmia transcription factor (MITF). Using Dct-lacZ transgenic mice, we measured the spatial and temporal pattern of Dct expression in vivo during neocortical neurogenesis in the brain. Dct was expressed in all layers of the dorsal telencephalon in E10.5. At E15.5 and E17.5 when cortical neurogenesis occurs, expression of Dct was primarily localized to the ventricular zone (VZ) where neuronal stem cells reside. Blocking endogenous Dct by RNAi decreased proliferation of embryonic cortical neural progenitor cells (by 48%, P < 0.05), as determined by BrdU incorporation. In adult brain, Dct/Dct expression decreased in the subventricular zone (SVZ), dentate gyrus and olfactory bulb (OB). However, strong expression of Dct was observed in rostral migratory stream (RMS) and septum. Overexpression of Dct in SVZ cells derived from the adult mice significantly increased the number of cells by 260%, whereas silencing Dct by RNAi decreased cell numbers by 25.8% at 48 h post-nucleofection (P < 0.05). The results of RT-PCR analysis revealed that Dct in the brain lacks exon 7 and is identical to the form of Dct found in neural-crest-derived melanocytes. Our data indicate that Dct, previously known as a melanoblast marker, regulates neural progenitor cell proliferation.

Animals↗
PubMed2006

Immune protection, natural products, and skin cancer: is there anything new under the sun?

Non-melanoma skin cancers such as squamous cell carcinoma and basal cell carcinoma are the most common types of human neoplasms, representing one third of all new malignancies diagnosed in the US. The number of new cases diagnosed per year in the US alone is approaching one million and continues to rise. Ultraviolet (UV) radiation from the sun is a major cause of non-melanoma skin cancer in humans. Aside from the mutagenic effects of UV radiation, there are suggestions from clinical studies and evidence in animal models that the immune system plays an important role in preventing skin cancer development and progression, and is suppressed by cutaneous exposure to UV radiation. In this article, we review the research on new and existing agents that are being developed to protect the skin immune response from suppression by UV radiation. We also discuss the current state of knowledge regarding their mechanism of action in humans as well as animal models of photosuppression, and their efficacy in cancer prevention.

Aloe↗
PubMed2004

Ethanol and aloe emodin alter the p53 mutational spectrum in ultraviolet radiation-induced murine skin tumors.

Mutations in the p53 tumor-suppressor gene contribute to the development of skin cancer, and the spectrum of mutations in this gene correlates with specific physical and chemical carcinogens in the environment. Cosmetics may contain alcohols and/or aloe emodin (AE). Although these compounds are not carcinogenic when applied to the skin, they may increase the carcinogenicity of ultraviolet (UV) radiation. We investigated whether ethanol (EtOH) and AE alone or combined with UV radiation cause mutations in the p53 gene. In the absence of UV radiation, C3H/HeN mice chronically treated for up to 33 wk with AE in 25% EtOH-in-water vehicle or vehicle alone failed to develop tumors and had no mutations in exons 4-8 of the p53 gene. UV radiation alone induced skin tumors, which had mutations predominantly in p53 exons 5 and 8. In contrast, mutations arising in UV + EtOH-or UV + AE-treated groups were more broadly distributed throughout the p53 gene. Mutations were found in exons 4, 6, and 7, as well as in exons 5 and 8. This altered distribution of mutations across the p53 DNA sequence more closely resembles the pattern observed in TP53 from human skin tumors at sun-exposed sites than that in the p53 gene of mice treated with UV alone. Thus, treatment with UV radiation in combination with two chemicals not thought to be carcinogenic, alcohol, and AE results in a broader distribution of mutations in a critical tumor-suppressor gene.

Animals↗
PubMed2004

Natural products as aids for protecting the skin's immune system against UV damage.

Modern sun-protection products reduce the risk for erythema and DNA damage, but even those products with a very high sun protection factor (SPF) and full-spectrum UVB and UVA protection may not prevent UV radiation (UVR)-induced immunomodulation. Formulating sunscreens with a high SPF, as well as a high immune protection factor, is necessary for preventing skin cancer and maintaining effective immune responses to infectious disease after sun exposure. Supplementing current sun-protection products with immunoprotective compounds may help fill the gap between erythema protection and immunoprotection. Animal and now human studies have shown that a class of agents known as oligosaccharins--complex carbohydrates found in plants--protect the cutaneous immune system from UVB-induced and UVA-induced immunomodulation. This immunoprotective effect occurs independently from erythema and DNA damage protection, and these agents, particularly tamarind xyloglucan, may become important adjunctive ingredients to sunscreens.

Aloe↗
PubMed2003

Molecular characterization of new melanoma cell lines from C3H mice induced by ethanol plus ultraviolet radiation.

A major obstacle in understanding the etiology of malignant melanoma is the lack of mouse models and transplantable cell lines. We have recently developed a model of primary melanoma in C3H mice induced by ethanol and UV light. The present study characterizes three cell lines, SM190.2, SM190.626, and SD0302, derived from two melanomas produced in the dorsal skin of two C3H mice treated thrice weekly for 28-33 weeks with UV radiation and ethanol. In both tumors, the N-ras oncogene was mutated. Tumor SM190 lacked exon 2 of the p16(INK4a) tumor suppressor gene. Cell line SM190.2, which was derived from tumor SM190, produced pigmented tumors when transplanted into syngeneic severe combined immunodeficient mice and normal mice. None of the cell lines produced metastases. All three cell lines were highly aneuploid, even at low passage numbers. SM190.2 and SD0302 cells contained an interstitial deletion in the long arm of chromosome 4, where the p16(INK4a) gene resides, and SM190.2 had an additional segment in chromosome 6. The third cell line, SM190.626, had three consistent Robertsonian translocation markers involving chromosomes 7, 14, and 17. The translocation involving mouse chromosome 14 may prove especially valuable because translocations in this chromosome are associated with metastatic behavior. These reagents will provide opportunities to search for new tumor suppressor genes that may contribute to the growth and metastasis of primary melanoma.

Animals↗