Moreover, MITF and TFEB proteins, directly regulate each other’s mRNA and protein expression while their subcellular localization and transcriptional activity are subject to similar modulation, such as the mTOR signaling pathway. UBC9 is a ubiquitin conjugating enzyme whose proteins associates with MITF. Although hUBC9 is known to act preferentially with SENTRIN/SUMO1, an in vitro analysis demonstrated greater actual association with MITF. hUBC9 is a critical regulator of melanocyte differentiation. To do this, it targets MITF for proteasome degradation. Protein kinase C-interacting protein 1 (PKC1) associates with MITF. Their association is reduced upon cell activation. When this happens MITF disengages from PKC1. PKC1 by itself, found in the cytosol and nucleus, has no known physiological function. It does, however, have the ability to suppress MITF transcriptional activity and can function as an in vivo negative regulator of MITF induced transcriptional activity. The functional cooperation between MITF and the lymphoid enhancing factor (LEF-1) results in a synergistic transactivation of the dopachrome tautomerase gene promoter, which is an early melanoblast marker. LEF-1 is involved in the process of regulation by Wnt signaling. LEF-1 also cooperates with MITF-related proteins like TFE3. MITF is a modulator of LEF-1, and this regulation ensures efficient propagation of Wnt signals in many cells. Translational regulation Translational regulation of MITF is still an unexplored area with only two peer-reviewed papers (as of 2019) highlighting the importance. During glutamine starvation of melanoma cells ATF4 transcripts increases as well as the translation of the mRNA due to eIF2α phosphorylation. This chain of molecular events leads to two levels of MITF suppression: first, ATF4 protein binds and suppresses MITF transcription and second, eIF2α blocks MITF translation possibly through the inhibition of eIF2B by eIF2α. MITF can also be directly translationally modified by the RNA helicase DDX3X. The 5' UTR of MITF contains important regulatory elements (IRES) that is recognized, bound and activated by DDX3X. Although, the 5' UTR of MITF only consists of a nucleotide stretch of 123-nt, this region is predicted to fold into energetically favorable RNA secondary structures including multibranched loops and asymmetric bulges that is characteristics of IRES elements. Activation of this cis-regulatory sequences by DDX3X promotes MITF expression in melanoma cells. See also Microphthalmia Splashed white References External links Transcription factors Gene expression Human proteins