Dynein Light Chain 1 (DYNLT1) Interacts with Normal and Oncogenic Nucleoporins

Abstract

The chimeric oncoprotein NUP98-HOXA9 results from the t(7;11)(p15;p15) chromosomal translocation and is associated with acute myeloid leukemia. It causes aberrant gene regulation and leukemic transformation through mechanisms that are not fully understood. NUP98-HOXA9 consists of an N-terminal portion of the nucleoporin NUP98 that contains many FG repeats fused to the DNA-binding homeodomain of HOXA9. We used a Cytotrap yeast two-hybrid assay to identify proteins that interact with NUP98-HOXA9. We identified Dynein Light Chain 1 (DYNLT1), an integral 14 KDa protein subunit of the large microtubule-based cytoplasmic dynein complex, as an interaction partner of NUP98-HOXA9. Binding was confirmed by in vitro pull down and co-immunoprecipitation assays and the FG repeat region of NUP98-HOXA9 was shown to be essential for the interaction. RNAi-mediated knockdown of DYNLT1 resulted in reduction of the ability of NUP98-HOXA9 to activate transcription and also inhibited the ability of NUP98-HOXA9 to induce proliferation of primary human hematopoietic CD34+ cells. DYNLT1 also showed a strong interaction with wild-type NUP98 and other nucleoporins containing FG repeats. Immunofluorescence analysis showed that DYNLT1 localizes primarily to the nuclear periphery, where it co-localizes with the nuclear pore complex, and to the cytoplasm. Deletion studies showed that the interactions of the nucleoporins with DYNLT1 are dependent predominantly on the C-terminal half of the DYNLT1. These data show for the first time that DYNLT1 interacts with nucleoporins and plays a role in the dysregulation of gene expression and induction of hematopoietic cell proliferation by the leukemogenic nucleoporin fusion, NUP98-HOXA9.

Age-associated genes in human mammary gland drive human breast cancer progression

“…DYNLT3 protein has been reported to form the light chain component of the cytoplasmic dynein motor protein complex [33,34]. Its paralog, DYNLT1, has been found to promote tumor progression [35][36][37]. Thus, our current study and the published studies indicate that cytoplasmic dynein motor proteins play a critical role in tumor progression.…”

<p>Effects of dynein light chain Tctex-type 3 on the biological behavior of ovarian cancer</p>

“…Additional studies have focused on the correlation between DYNLT1 and cancer. Sarma et al14 found that DYNLT1 interacted with nucleopore proteins, which play a role in the dysregulation of gene expression and the proliferation of hematopoietic cells. Cervantes et al15 revealed that the DYNLT1 exhibited significantly increased expression in liver cancer and participated in the progression of liver cancer.…”

Intranuclear dynamics of the Nup107-160 complex

“…Although still debated, the aberrant localization and function of the chimeras, as well as their interaction with endogenous Nup98, appear to contribute to leukemogenesis (reviewed in Gough et al. , 2011 ; Franks and Hetzer, 2013 ; see also Sarma and Yaseen, 2013 ; Salsi et al. , 2014 ).…”