Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Although cyclophilin A (CyP-A) is a relatively abundant small immunophilin present in the cytoplasm of all mammalian cells, its general function(s) in the absence of the immunosuppressant drug cyclosporin A is not known. In contrast, the high molecular weight hsp90-binding immunophilins appear to play a role in protein trafficking in that they have been shown to link glucocorticoid receptor-hsp90 and p53.hsp90 complexes to the dynein motor protein for retrograde movement along microtubules. These immunophilins link to cytoplasmic dynein indirectly through the association of the immunophilin peptidylprolyl isomerase (PPIase) domain with dynamitin, a component of the dynein-associated dynactin complex (Galigniana, M. D., Harrell, J. M., O'Hagen, H. M., Ljungman, M., and Pratt, W. B. (2004) J. Biol. Chem. 279, 22483-22489). Here, we show that CyP-A exists in native heterocomplexes containing cytoplasmic dynein that can be formed in cell-free systems. Prolyl isomerase activity is not required for forming the dynein complex, but the PPIase domain fragment of FKBP52 blocks complex formation and CyP-A binds to dynamitin in a PPIase domain-dependent manner. CyP-A heterocomplexes containing tubulin and dynein can be formed in cytosol prepared under microtubule-stabilizing conditions, and CyP-A colocalizes in mouse fibroblasts with microtubules. Colocalization with microtubules is disrupted by overexpression of the PPIase domain fragment. Thus, we conclude that CyP-A associates in vitro and in vivo with the dynein/dynactin motor protein complex and we suggest that CyP-A may perform a general function related to the binding of cargo for retrograde movement along microtubules.
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PMID:Cyclophilin-A is bound through its peptidylprolyl isomerase domain to the cytoplasmic dynein motor protein complex. 1549 17

Increased survival, differentiation, and apoptotic death are common mechanisms relevant for both cancer and neurodegenerative diseases. Although these disorders are characterized by different manifestations, it appears that a common mechanism may be present which directs the fate of a cell to either degeneration or proliferation. There are two classes of proteins that have been extensively investigated in these diseases but their possible interaction during signal transduction has not been studied. Prolyl isomerase Pin1 is an enzyme which translates Ser/Thr-Pro phosphorylation into conformational changes able to modify the activities of its substrates. Its role in cancer development has been linked to its capacity to induce conformational changes to the tumor suppressor gene p53. Neurotrophins belong to a family of proteins that induce opposite effects on neuronal cells such as increased survival, development, and function. According to their function, alteration of these proteins during neurodegenerative processes has been investigated and reported in a number of experimental paradigms involving animal models and humans. However, in recent years, it has been shown that Pin1 downregulation is present in neurodegenerative disorders, while increased expression of neurotrophins and their receptors is found in certain types of cancer and correlate with poor prognosis. Notably, at the level of signal transduction, Pin1 and neurotrophin activity regulate the outcome of similar pathways such as proline-directed kinase and, most importantly, p53 signaling. Thus the possible existence of a loop between Pin1 and neurotrophins was investigated to understand the pathogenesis of these diseases.
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PMID:Prolyl isomerase Pin1 and neurotrophins: a loop that may determine the fate of cells in cancer and neurodegeneration. 2820 98