Makorin RING Finger Protein 1 (MKRN1) Has Negative and Positive Effects on RNA Polymerase II-Dependent Transcription

Abstract

Through its transcriptional activities, the proto-oncoprotein c-Jun can regulate cellular proliferation, survival, and differentiation. We have established a novel yeast assay that screens for repressors of c-Jun transcriptional activity. This screen led to the identification of a ubiquitously expressed novel RING zinc finger protein, termed Makorin RING zinc finger protein 1 (MKRN1), recently shown to act as an E3 ubiquitin ligase. Overexpression of MKRN1 in mammalian cells inhibited the transcriptional activities of not only c-Jun, but also the nuclear receptors, the androgen receptor, and the retinoic acid receptors. Truncation analysis indicates that both the amino and carboxy termini are required for this transrepression activity. Surprisingly, when fused to the heterologous DNAbinding domain of GAL4, MKRN1 activates, rather than inhibits, a GAL4-responsive reporter plasmid. In addition, truncation of either the amino- or carboxy-terminal half of MKRN1 disrupts its transactivation activity, the same observation that was made on its transrepression activity. These results demonstrate that MKRN1 has transcriptional activity and suggest that its transrepression and transactivation functions are mediated by the same mechanism. Interestingly, disruption of MKRN1's ubiquitin ligase activity does not affect its inhibitory transcriptional activity. Thus, MKRN1 may represent a nuclear protein with multiple nuclear functions, including regulating RNA polymerase II-catalyzed transcription.

Suppression of PPARγ through MKRN1-mediated ubiquitination and degradation prevents adipocyte differentiation

“…[21][22][23][24][25] It may also function as a regulator of nuclear receptors, including androgen and retinoic acid receptors, independent of E3 ligase activities. 26 In this study, we report that MKRN1 may mediate PPARg2 ubiquitination and proteasome-dependent degradation. The physiological function of MKRN1 in negative regulation of PPARg2 protein was further demonstrated using MKRN1 knockout MEFs, 3T3-L1, and C3H10T1/2 cell lines, indicating that MKRN1 is a potential new therapeutic target in PPARgrelated diseases.…”

“…In previous studies, MKRN1 was shown to repress the transcriptional activities of nuclear receptors such as androgen and retinoic acid receptors. 26 This finding prompted us to investigate whether MKRN1 also has regulatory effects on the transcriptional activities of PPARg, a nuclear receptor responsible for adipocyte differentiation. 27 The effects of MKRN1 on PPARg2 were examined by co-transfecting H1299 human lung cancer cells with plasmids expressing PPARg2 and PPRE-luciferase reporter in the presence or absence of troglitazone, an agonist of PPARg2.…”

Makorin Ring Zinc Finger Protein 1 (MKRN1), a Novel Poly(A)-binding Protein-interacting Protein, Stimulates Translation in Nerve Cells

“…As an E3 ubiquitin ligase it acts on itself and the catalytic subunit of human telomerase reverse transcriptase (26), p53 and p21 (27). Furthermore, MKRN1 modulates RNA polymerase II-mediated transcription (28) and may play a role in mRNA decay (29).…”

MKRN1 Induces Degradation of West Nile Virus Capsid Protein by Functioning as an E3 Ligase

“…The role of MKRN1 as an E3 ligase was first identified by its ability to degrade hTERT (16). Interestingly, MKRN1 functions as a coregulator of androgen and retinoic acid receptor (27), suggesting possible diverse roles of MKRN1 in human cells.…”