Disease relevance of MLPH

• In breast tumor tissue specimens, expression of ln alpha 3 and beta 3 mRNAs tended to be reduced relative to levels observed in adjacent nontumor tissue, whereas in gamma 2 levels were elevated in specimens with increased amounts of myoepithelial cells [1].
• The combination of Ida/Bu/Melph appears a promising alternative regimen for PBSCT in myeloma, with low transplant-related toxicity and fast hematological recovery [2].

High impact information on MLPH

• Other regions of Mlph reported to interact with MyoVa globular tail, actin, or EB1 are not essential for melanosome transport rescue [3].
• Melanophilin (Mlph) regulates retention of melanosomes at the peripheral actin cytoskeleton of melanocytes, a process essential for normal mammalian pigmentation [3].
• A coiled-coil domain of melanophilin is essential for Myosin va recruitment and melanosome transport in melanocytes [3].
• We developed a novel melanosome transport assay using a Mlph-null cell line to study formation of the active Rab27a:Mlph:MyoVa complex [3].
• Mlph is proposed to be a modular protein binding the melanosome-associated protein Rab27a, Myosin Va (MyoVa), actin, and microtubule end-binding protein (EB1), via distinct N-terminal Rab27a-binding domain (R27BD), medial MyoVa-binding domain (MBD), and C-terminal actin-binding domain (ABD), respectively [3].

Biological context of MLPH

• A homozygous single-base deletion in MLPH causes the dilute coat color phenotype in the domestic cat [4].
• Single-nucleotide polymorphism analyses in dilute individuals identified a single haplotype in dilute cats, suggesting that a single mutation event in MLPH gave rise to dilute in domestic cats [4].
• Sequence analysis in dilute cats identified a single base pair deletion in exon 2 of MLPH transcripts that introduces a stop codon 11 amino acids downstream, resulting in the truncation of the bulk of the MLPH protein [4].
• RESULTS: We sequenced the canine MLPH gene and performed a mutation analysis of the MLPH exons in 6 Doberman Pinschers and 5 German Pinschers [5].
• Fine-mapping identified a genomic region exhibiting conserved synteny to human chromosome 2, which included one of the three dilute candidate genes, melanophilin (MLPH) [4].

Anatomical context of MLPH

• Myosin Va isoforms containing exon F are able to colocalize with and influence melanosome distribution by indirect interaction with rab27a and direct interaction with melanophilin [6].
• Rab27 acts through organelle-specific effector proteins, such as granuphilin in pancreatic beta cells and melanophilin in melanocytes [7].
• The effect of benzamide (B) and 3-aminobenzamide (3-AB) on sister chromatid exchanges (SCEs) and cell kinetics induced in vitro by melphalan (MELPH) or thiotepa (THIO) was studied in normal human lymphocytes [8].

Associations of MLPH with chemical compounds

• The combined treatments with either CBC or MELPH or MMC and nicotinamide showed the potentiating ability of the latter drug [9].
• Theophylline and MELPH were also found to act synergistically on the induction of SCEs [9].
• The effects of nicotinamide on SCE rates induced in vitro by chlorambucil (CBC or melphalan (MELPH) or mitomycin C (MMC) was studied [9].
• The combined treatments with either MELPH or THIO plus B or 3-AB showed the potentiating ability on SCE rates and the ability to induce cell division delays of the latter chemicals [8].

Physical interactions of MLPH

• Here, we show by reconstitution using purified proteins that Rab27a and Mlph are sufficient to form a transport complex with myosin Va in vitro [10].

Other interactions of MLPH

• Our immunofluorescence and yeast two-hybrid screening studies reveal that Rab27b can form a tripartite complex on the melanosome membrane with Melanophilin, a Rab27a effector, and protein products of Myosin Va transcripts that contain exon F [11].
• In the retinal pigment epithelium, a similar complex formed by Rab27a, a melanophilin homolog called MyRIP and myosin VIIa is probably responsible for the tethering of melanosomes to the actin cytoskeleton [12].
• RH mapping of the canine MLPH gene was performed using an STS marker derived from BAC sequences [13].

Analytical, diagnostic and therapeutic context of MLPH

• In our study comparing Cy and TBI with Melph and TBI in AML, we have shown a significant increase in antileukemic activity after transplantation following the latter conditioning regimen [14].
• In the single-arm ALL autograft study our results were very encouraging and suggest that Melph/TBI can produce disease-free survival results at least as good as with other conditioning regimens [14].

References