Disease relevance of Fxyd1

• Hypertrophy, increased ejection fraction, and reduced Na-K-ATPase activity in phospholemman-deficient mice [1].
• The fusion protein PML-RARalpha, generated by the t(15;17)(q22;q11.2) translocation associated with acute promyelocytic leukemia (APL), initiates APL when expressed in the early myeloid compartment of transgenic mice [2].
• Leukemias that arose from doubly transgenic mice were less mature than those from PML-RARalpha transgenic mice, but they both responded to all-trans retinoic acid in vitro [3].
• We here investigate the in vivo effects of intermittent hypoxia on syngenic grafts of leukemic blasts in a PML-RARalpha transgenic mouse model of AML [4].
• Adenovirus-mediated expression of PML suppresses growth and tumorigenicity of prostate cancer cells [5].

High impact information on Fxyd1

• The PML gene of acute promyelocytic leukaemia (APL) encodes a cell growth and tumour suppressor, however, the mechanisms by which PML suppresses tumorigenesis are poorly understood [6].
• Here we report that the proto-oncogene product PML induces expression of LMP-2, LMP-7, TAP-1 and TAP-2 in an MHC-class I-negative, recurrent tumour, leading to the re-expression of cell-surface MHC in tumours and to rejection of the tumours [7].
• Proto-oncogene PML controls genes devoted to MHC class I antigen presentation [7].
• PML also regulates MHC expression in untransformed fibroblasts [7].
• Role of PML in cell growth and the retinoic acid pathway [8].

Chemical compound and disease context of Fxyd1

• An in vitro deficit in the VIP inhibitory response to ACh challenge is apparent in PLM with distal colonic aganglionosis [9].

Biological context of Fxyd1

• Phospholemman (FXYD1), a 72-amino acid transmembrane protein abundantly expressed in the heart and skeletal muscle, is a major substrate for phosphorylation in the cardiomyocyte sarcolemma [1].
• PLM likely plays a role in muscle contractility and cell volume regulation through its function as a channel or a channel regulator [10].
• The 3' untranslated domains of mouse PLM cDNA clones show sequence differences not accounted for by alternative splicing [10].
• We cloned the murine PLM cDNA and used it as a probe to isolate the gene from a 129/SvJ genomic library [10].
• A gene family of small membrane proteins, represented by phospholemman and the gamma subunit of Na,K-ATPase, was defined and characterized by the analysis of more than 1000 related ESTs (expressed sequence tags) [11].

Anatomical context of Fxyd1

• Tissue expression of murine PLM parallels that in other species, being highest in heart, skeletal muscle, and liver [10].
• In WT myocytes, 1 micromol/L isoproterenol (ISO) increased PLM phosphorylation and stimulated NKA activity mainly by increasing its affinity for internal Na (Km decreased from 18.8+/-1.4 to 13.6+/-1.5 mmol/L), with no significant effect on the maximum pump rate [12].
• When GFP was fused to PML protooncogene product, fluorescence was detected in a unique nuclear organelle pattern indistinguishable from that of PML protein, showing the potential use of GFP as a fluorescent tag [13].
• The cell line retains expression of PML-RARalpha and is approximately 33-fold more resistant than the parental counterpart to the apoptogenic effects of the retinoid [14].
• Remarkably, however, the expression level of PML-RARalpha in bone marrow cells or APL cells was less than 3% of that measured in the low-penetrance transgenic model [15].

Associations of Fxyd1 with chemical compounds

• PML function was essential for the tumor-growth-suppressive activity of retinoic acid (RA) and for its ability to induce terminal myeloid differentiation of precursor cells [8].
• To investigate the role of oligomerization for the transformation potential of X-ABL and for the sensitivity to STI571, we constructed ABL chimeras with oligomerization interfaces of proteins involved in leukemia-associated translocations such as BCR, TEL, PML, and PLZF [16].
• These results suggest that PLM phosphorylated at serine 68 inhibited I(NaCa) [17].
• Mutating serine 68 to glutamic acid (phosphomimetic) resulted in additional suppression of I(NaCa) as compared with wild-type PLM [17].
• Mutating serine 63 to alanine (S63A) preserved the sensitivity of PLM to forskolin in terms of suppression of I(NaCa), whereas mutating serine 68 to alanine (S68A) abolished the inhibitory effect of PLM on I(NaCa) [17].

Other interactions of Fxyd1

• We conclude that PLM modulates the NKA function in a manner similar to the way phospholamban affects the related SR Ca-ATPase (inhibition of transport substrate affinity, that is relieved by phosphorylation) [12].
• It is a member of the FXYD family of single-span transmembrane proteins that include phospholemman, Mat-8, and the gamma-subunit of Na(+)-K(+)-ATPase [18].

Analytical, diagnostic and therapeutic context of Fxyd1

• Immunofluorescence localization studies suggested that the cleavage of PML-RARalpha must occur within the cell, and perhaps, within the nucleus [2].
• A tumorigenicity test in nude mice showed that the Ad-PML-treated DU145 cells failed to form tumors [5].
• In this study, we further explored the possibility of applying PML as a potential agent for developing prostate cancer gene therapy using an adenovirus delivery system [5].
• Western blots of cell extracts revealed that strain mit1Delta contained no PLM [19].
• TauT and PLM genes were demonstrated by RT-PCR in the caput of +/- and c-ros knockout males [20].

References