The protein neural retina leucine zipper (Nrl) is a basic motif-leucine zipper transcription factor that is preferentially expressed in rod photoreceptors. It acts synergistically with Crx to regulate rhodopsin transcription. Missense mutations in human NRL have been associated with autosomal dominant retinitis pigmentosa. Here we report that deletion of Nrl in mice results in the complete loss of rod function and super-normal cone function, mediated by S cones. The photoreceptors in the Nrl-/- retina have cone-like nuclear morphology and short, sparse outer segments with abnormal disks. Analysis of retinal gene expression confirms the apparent functional transformation of rods into S cones in the Nrl-/- retina. On the basis of these findings, we postulate that Nrl acts as a 'molecular switch' during rod-cell development by directly modulating rod-specific genes while simultaneously inhibiting the S-cone pathway through the activation of Nr2e3.

Crx is a novel paired-like homeodomain protein that is expressed predominantly in retinal photoreceptors and pinealocytes. Its gene has been mapped to chromosome 19q13.3, the site of a disease locus for autosomal dominant cone-rod dystrophy (CORDII). Analysis of the proband from a family with autosomal dominant CORD revealed an Arg41Trp substitution in the third residue of the CRX homeodomain. The sequence change cosegregated with the disease phenotype and was not detected in 247 normal controls. Recombinant CRX homeodomain containing the Arg41Trp substitution showed decreased DNA binding activity. Analysis of another 169 CORD probands identified three additional CRX sequence variations (Arg41Gln, Val242Met, and a 4 bp deletion in codons 196/7) that were not found among the controls. This data suggests that mutations in the CRX gene are associated with photoreceptor degeneration and that the Crx protein is necessary for the maintenance of normal cone and rod function.

NRL, a bZIP transcription factor of the Maf subfamily, interacts with the homeodomain protein CRX and synergistically regulates rhodopsin expression. Here we report that six isoforms of NRL (29 -35 kDa) are generated by phosphorylation and expressed specifically in the mammalian retina. The anti-NRL antibody also crossreacts with a cytosolic 45-kDa protein, which is detected in neuronal tissues but is not encoded by the NRL gene. In both human retinal cell cultures and sections of fetal and adult human retina, NRL is present in the nuclei of developing and mature rods but not cones. We propose that NRL regulates rod photoreceptor-specific gene expression and is involved in rod differentiation.Retinal photoreceptors are highly specialized neurons that capture photons and convert them to chemical signals. Humans and Old World primates have four distinct photoreceptor types, each with a specific visual pigment (1) and a characteristic retinal distribution (2). Rhodopsin is the photopigment in rod photoreceptors, which dominate primate retina. Rhodopsin provides high sensitivity, but the rod synaptic circuitry yields low spatial resolution. The red, green, and blue visual pigments define the three cone types, whose neural circuits mediate color vision and high spatial resolution but require bright light.Extensive anatomical, lineage, and birth dating studies have demonstrated that the genesis of specific photoreceptor types from retinal progenitors is guided by intrinsic genetic programs, inductive cell-cell interactions, and extrinsic factors (3-6). Postmitotic neurons committed to a photoreceptor cell fate exhibit varying delays before expressing their cell typespecific photopigment, suggesting that the specification of a differentiated rod or cone phenotype requires additional cues (7-10). It is envisaged that these inductive cues turn on a "molecular switch," which leads to expression of a specific visual pigment and other components of the transduction machinery.Cell type-specific gene expression is achieved by combinatorial and synergistic actions of specific activator proteins that recruit the basal transcription machinery to the promoter region (11, 12). Several transcription factor genes are expressed in retina (13-17), and a number of cis-regulatory elements have been identified in retinal gene promoters (18 -20). However, only two transcription factors, NRL and CRX, have so far been implicated directly in modulating photoreceptor-specific gene expression. NRL was isolated from a subtracted human retinal cDNA library and encodes a basic motif-leucine zipper (bZIP) protein (21). It displays strong homology to Maf proteins, which are involved in differentiation and gene regulation (22). NRL was the first transcription factor shown to bind to a cis-regulatory sequence (called NRE or NRL response element) in the rhodopsin promoter and transactivate its activity in cultured cells (23,24). CRX is a photoreceptor-and pineal-specific homeodomain protein that appears to modulate several retinal gene promoters (25-2...

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The retinitis pigmentosa GTPase regulator (RPGR) gene encodes a protein homologous to the RCC1 guanine nucleotide exchange factor and is mutated in 20% of patients with X-linked retinitis pigmentosa. We have characterized the full-length and variant cDNAs corresponding to the mouse homolog of the RPGR gene (mRpgr). Comparison with the human cDNA revealed sequence identity primarily in the region of RCC1 homology repeats. As in humans, the mRpgr gene maps within 50 kilobases from the 5-end of the Otc gene. The mRpgr transcripts are detected as early as E7 during embryonic development and are expressed widely in the adult mice. Variant mRpgr isoforms are generated by alternative splicing and by utilizing two in-frame initiation codons. The products of mRpgr cDNAs migrate aberrantly in SDS-polyacrylamide gels because of a charged domain. In transfected COS cells, the mRpgr protein is isoprenylated and is localized in the Golgi complex. This subcellular distribution is not observed after treatments with brefeldin A or mevastatin and when the conserved isoprenylation sequence (CTIL) at the carboxyl terminus is deleted or mutagenized. These studies suggest a role for the mRpgr protein in Golgi transport and form the basis for investigating the mechanism of photoreceptor degeneration in X-linked retinitis pigmentosa. Retinitis pigmentosa (RP)1 refers to a group of retinal degeneration disorders characterized by night blindness, progressive loss of peripheral vision, and a characteristic pigmentary retinopathy (1). In addition to wide variations in clinical phenotype, RP exhibits extensive genetic heterogeneity; more than 15 distinct genetic loci have been localized to human chromosomes, and mutations in a large number of genes have been associated with inherited retinal degeneration (2; also see RetNet web site www.sph.uth.tmc.edu/www/utsph/RetNet/disease.htm). Patients and carriers with X-linked forms of RP (XLRP) demonstrate severe clinical manifestations and account for 7-30% of the RP population (3, 4). Two major XLRP loci, RP2 and RP3, have been mapped to Xp11.3-p11.23 and Xp21.1, respectively; of these, RP3 is the more common form accounting for 70% of XLRP (4, 5). Sequencing of the genomic DNA spanning small deletions in RP3 patients revealed a novel gene, RPGR (retinitis pigmentosa GTPase regulator), which is shown to be mutated in 20% of XLRP families (6 -8). As yet unidentified exon(s) in the RPGR gene and/or another gene in the RP3 region have been suggested as possibilities for the relatively low frequency of observed mutations.RPGR transcripts appear to be present in all tissues, although expression levels were barely detectable in retina and retinal pigment epithelium, thought to be the primary sites of disease manifestation in XLRP. The putative RPGR gene product of 815 amino acids contains six tandem repeats that show a high degree of homology to the RCC1 protein, a GEF for RanGTPase (9). It was, therefore, proposed that the RPGR gene product functions as a GEF for Ran or a Ran-like protein in the retin...

The protective antigen (PA) protein of anthrax toxin binds to a cellular receptor and is cleaved by cell surface furin to produce a 63-kDa fragment (PA63). The receptor-bound PA63 oligomerizes to a heptamer and acts to translocate the catalytic moieties of the toxin, lethal factor (LF) and edema factor (EF), from endosomes to the cytosol. In this report, we used nondenaturing gel electrophoresis to show that each PA63 subunit in the heptamer can bind one LF molecule. Studies using PA immobilized on a plastic surface showed that monomeric PA63 is also able to bind LF. The internalization of PA and LF by cells was studied with radiolabeled and biotinylated proteins. Uptake was relatively slow, with a half-time of 30 min. The number of moles of LF internalized was nearly equal to the number of moles of PA subunit internalized. The essential role of PA oligomerization in LF translocation was shown with PA protein cleaved at residues 313-314. The oligomers formed by these proteins during uptake into cells were not as stable when subjected to heat and detergent as were those formed by native PA. The results show that the structure of the toxin proteins and the kinetics of proteolytic activation, LF binding, and internalization are balanced in a way that allows each PA63 subunit to internalize an LF molecule. This set of proteins has evolved to achieve highly efficient internalization and membrane translocation of the catalytic components, LF and EF.

Studies on post-translational modifications (PTMs) have grabbed attention of the scientific community worldwide, its role in pathogenesis of cancer and prognostic biomarkers associated with cancers. However, unraveling the specific role of PTMs in carcinogenesis or in predictive biomarkers requires holistic understanding of the cancer types and associated mechanisms. Manifestation of cancer is complex and involves multiple steps including modifications at the levels of genes, associated proteins and signaling pathways. Biomarkers, as a prognostic marker, are critical in deciding efficacy of the clinical outcomes in malignancies. Growing evidence suggests that several biomarkers that are post-translationally modified play important role in human cancers. In the current review, few of such biomarkers and targets that are post-translationally modified and are associated with carcinogenesis are collated and analyzed to provide a bird's eye view of their role in cancer types. Such analysis will help in understanding the pathogenesis and the precise role of biomarkers in designing better therapeutic interventions for different cancer types. METHODS The writing of this review involved a comprehensive search of original articles and reviews published on the subject of post translational modifications. Free search engine PubMed was used to conduct the online search. Sorting option 'Best Match' of PubMed was used to conduct the more relevant search.Various expressions were used to find relevant references for example, "post translational modifications in cancer", "acetylation in cancer and post translational modifications", "methylation in cancer and post translational modifications", "biomarkers in cancer" etc. Some other expressions were used to conduct a more specific search to complement the findings in the articles retrieved with the more general search criteria for example, "checkpoint kinase 1 in cancer", "candidate tumor suppressor BTG3" etc. Further, some articles were also found through reading of previous reviews on similar subjects including the ones by Karve and Cheema [1], and Han et al, [2].Articles clearly related to the theme of this review and those that matched the search criteria were selected according to their year of publication (only articles published after

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