The PICALM protein plays a key role in iron homeostasis and cell proliferation.
The PICALM protein plays a key role in iron homeostasis and cell proliferation.
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DOI：
10.1371/journal.pone.0044252
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Wechsler DS
中科院分区：
文献类型：
--
作者：
Scotland PB;Heath JL;Conway AE;Porter NB;Armstrong MB;Walker JA;Klebig ML;Lavau CP;Wechsler DS
广泛表达的磷脂酰肌醇结合蛋白结合蛋白(PICALM)与细胞膜结合，与蛋白结合，在蛋白介导的胞吞作用中发挥作用。人类PICALM基因的改变在侵袭性血液系统恶性肿瘤中存在，全基因组关联研究最近将PICALM基因与晚发性阿尔茨海默病联系起来。小鼠体内PICALM基因的失活和低形态突变会导致不同程度的贫血、铁代谢异常、生长迟缓和寿命缩短。为了了解PICALM的功能，我们研究了PICALM过表达的后果，并鉴定了来自突变FIT1小鼠的PICALM缺陷细胞。我们的结果确定了PICALM在转铁蛋白受体(TFR)内化中的作用，并证明了C端的PICALM残基对于它与clathrin的结合以及PICALM过表达对TFR内化的抑制作用是至关重要的。缺乏PICALM的小鼠胚胎成纤维细胞(MEF)表现出铁缺乏的几个特征(表面TFR表达增加，细胞内铁水平降低，细胞增殖减少)，所有这些都可以通过逆转录病毒PICALM表达来挽救。缺乏PICALM的细胞的增殖缺陷至少部分是由于铁摄取不足造成的，因为它可以通过补充铁来纠正。此外，缺乏PICALM的细胞对铁螯合特别敏感。综上所述，这些数据揭示了PICALM在铁稳态中的关键作用，并为PICALM相关疾病的发病机制提供了新的视角。
The ubiquitously expressed phosphatidylinositol binding clathrin assembly (PICALM) protein associates with the plasma membrane, binds clathrin, and plays a role in clathrin-mediated endocytosis. Alterations of the human PICALM gene are present in aggressive hematopoietic malignancies, and genome-wide association studies have recently linked the PICALM locus to late-onset Alzheimer's disease. Inactivating and hypomorphic Picalm mutations in mice cause different degrees of severity of anemia, abnormal iron metabolism, growth retardation and shortened lifespan. To understand PICALM’s function, we studied the consequences of PICALM overexpression and characterized PICALM-deficient cells derived from mutant fit1 mice. Our results identify a role for PICALM in transferrin receptor (TfR) internalization and demonstrate that the C-terminal PICALM residues are critical for its association with clathrin and for the inhibitory effect of PICALM overexpression on TfR internalization. Murine embryonic fibroblasts (MEFs) that are deficient in PICALM display several characteristics of iron deficiency (increased surface TfR expression, decreased intracellular iron levels, and reduced cellular proliferation), all of which are rescued by retroviral PICALM expression. The proliferation defect of cells that lack PICALM results, at least in part, from insufficient iron uptake, since it can be corrected by iron supplementation. Moreover, PICALM-deficient cells are particularly sensitive to iron chelation. Taken together, these data reveal that PICALM plays a critical role in iron homeostasis, and offer new perspectives into the pathogenesis of PICALM-associated diseases.
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影响因子：
30.8
作者：
Harold, Denise;Abraham, Richard;Hollingworth, Paul;Sims, Rebecca;Gerrish, Amy;Hamshere, Marian L.;Pahwa, Jaspreet Singh;Moskvina, Valentina;Dowzell, Kimberley;Williams, Amy;Jones, Nicola;Thomas, Charlene;Stretton, Alexandra;Morgan, Angharad R.;Lovestone, Simon;Powell, John;Proitsi, Petroula;Lupton, Michelle K.;Brayne, Carol;Rubinsztein, David C.;Gill, Michael;Lawlor, Brian;Lynch, Aoibhinn;Morgan, Kevin;Brown, Kristelle S.;Passmore, Peter A.;Craig, David;McGuinness, Bernadette;Todd, Stephen;Holmes, Clive;Mann, David;Smith, A. David;Love, Seth;Kehoe, Patrick G.;Hardy, John;Mead, Simon;Fox, Nick;Rossor, Martin;Collinge, John;Maier, Wolfgang;Jessen, Frank;Schuermann, Britta;van den Bussche, Hendrik;Heuser, Isabella;Kornhuber, Johannes;Wiltfang, Jens;Dichgans, Martin;Froelich, Lutz;Hampel, Harald;Huell, Michael;Rujescu, Dan;Goate, Alison M.;Kauwe, John S. K.;Cruchaga, Carlos;Nowotny, Petra;Morris, John C.;Mayo, Kevin;Sleegers, Kristel;Bettens, Karolien;Engelborghs, Sebastiaan;De Deyn, Peter P.;Van Broeckhoven, Christine;Livingston, Gill;Bass, Nicholas J.;Gurling, Hugh;McQuillin, Andrew;Gwilliam, Rhian;Deloukas, Panagiotis;Al-Chalabi, Ammar;Shaw, Christopher E.;Tsolaki, Magda;Singleton, Andrew B.;Guerreiro, Rita;Muehleisen, Thomas W.;Noethen, Markus M.;Moebus, Susanne;Joeckel, Karl-Heinz;Klopp, Norman;Wichmann, H-Erich;Carrasquillo, Minerva M.;Pankratz, V. Shane;Younkin, Steven G.;Holmans, Peter A.;O'Donovan, Michael;Owen, Michael J.;Williams, Julie
通讯作者：
Williams, Julie
DOI：
10.1523/jneurosci.2471-08.2008
发表时间：
2008-10-08
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Bushlin I;Petralia RS;Wu F;Harel A;Mughal MR;Mattson MP;Yao PJ
通讯作者：
Yao PJ
DOI：
10.1073/pnas.93.10.4804
发表时间：
1996-05-14
影响因子：
11.1
作者：
Dreyling, MH;MartinezCliment, JA;Bohlander, SK
通讯作者：
Bohlander, SK
影响因子：
4.8
作者：
Hao, WH;Luo, Z;Lafer, EM
通讯作者：
Lafer, EM
影响因子：
4.2
作者：
CONNOR, JR;SNYDER, BS;MUFSON, EJ
通讯作者：
MUFSON, EJ