Androgens have been hypothesized to influence risk of breast cancer through several possible mechanisms, including their conversion to estradiol and their binding to the estrogen receptor and/or androgen receptor (AR) in the breast. The CAG repeat polymorphism in AR exon 1 has been implicated in breast cancer risk; however, studies on the association between this polymorphism and breast cancer risk remain conflicting. In order to derive a more precise estimation of the relationship, a large population-based case-control study was performed. We found that a long CAG sequence has a protective effect on breast cancer using an a priori determined cutoff (< 22 or ≥ 22) in a dominant model analysis [SL-LL vs. SS, odds ratio (OR) = 0.86, 95% confidence intervals (CI): 0.67-1.10]. A similar result was obtained by analyzing seven detailed genotyping case-control studies by allele comparison in dominant and recessive models. However, larger scale primary study is required to further evaluate the interaction of AR CAG polymorphism and breast cancer risk.
Cilia are key regulators of animal development and depend on intraflagellar transport (IFT) proteins for their formation and function, yet the roles of individual IFT proteins remain unclear. We examined the Ift56 hop mouse mutant and reveal novel insight into the function of IFT56, a poorly understood IFTB protein. Ift56 hop mice have normal cilia distribution but display defective cilia structure, including abnormal positioning and number of ciliary microtubule doublets. We show that Ift56 hop cilia are unable to accumulate Gli proteins efficiently, resulting in developmental patterning defects in Shh signaling-dependent tissues such as the limb and neural tube. Strikingly, core IFTB proteins are unable to accumulate normally within Ift56 hop cilia, including IFT88, IFT81 and IFT27, which are crucial for key processes such as tubulin transport and Shh signaling. IFT56 is required specifically for the IFTB complex, as IFTA components and proteins that rely on IFTA function are unaffected in Ift56 hop cilia. These studies define a distinct and novel role for IFT56 in IFTB complex integrity that is crucial for cilia structure and function and, ultimately, animal development.
Members of the Amyloid Precursor Protein (APP) family have important functions during neuronal development. However, their physiological functions in the mature nervous system are not fully understood. Here we use the C. elegans GABAergic motor neurons to study the postdevelopmental function of the APP-like protein APL-1 in vivo. We find that apl-1 has minimum roles in the maintenance of gross neuron morphology and function. However, we show that apl-1 is an inhibitor of axon regeneration, acting on mature neurons to limit regrowth in response to injury. The small GTPase Rab6/RAB-6.2 also inhibits regeneration, and does so in part by maintaining protein levels of APL-1. To inhibit regeneration, APL-1 functions via the E2 domain of its ectodomain; the cytoplasmic tail, transmembrane anchoring, and the E1 domain are not required for this function. Our data defines a novel role for APL-1 in modulating the neuronal response to injury.
Cilia are key regulators of animal development and depend on intraflagellar transport (IFT) proteins for their formation and function, yet the roles of individual IFT proteins remain unclear. We examined the Ift56 hop mouse mutant and reveal novel insight into the function of IFT56, a poorly understood IFTB protein. Ift56 hop mice have normal cilia distribution but display defective cilia structure, including abnormal positioning and number of ciliary microtubule doublets. We show that Ift56 hop cilia are unable to accumulate Gli proteins efficiently, resulting in developmental patterning defects in Shh signaling-dependent tissues such as the limb and neural tube. Strikingly, core IFTB proteins are unable to accumulate normally within Ift56 hop cilia, including IFT88, IFT81 and IFT27, which are crucial for key processes such as tubulin transport and Shh signaling. IFT56 is required specifically for the IFTB complex, as IFTA components and proteins that rely on IFTA function are unaffected in Ift56 hop cilia. These studies define a distinct and novel role for IFT56 in IFTB complex integrity that is crucial for cilia structure and function and, ultimately, animal development.
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