Biology subjects

Cruz, N. M.

Publications and source records attributed to Cruz, N. M..

3 recordsLinked to original sources

bioRxiv2026

Intermolecular 3'UTR-3'UTR interactions drive Wnt gene activation through heteromeric protein assembly

Stem cell differentiation depends on transcription factors that are often encoded by mRNAs with highly conserved 3'UTRs. To determine their functional roles, we performed 3'UTR loss-of-function studies. Partial deletion of endogenous 3'UTRs altered stem cell differentiation efficiency in 7/10 cases. As 6/7 3'UTR deletions did not affect expression level of the encoded proteins, we reveal widespread abundance-independent regulatory roles of 3'UTRs. For example, 3'UTR deletion of CTNNB1, an mRNA that encodes the essential Wnt co-activator {beta}-catenin, keeps {beta}-catenin levels unaffected but impairs zebrafish embryogenesis and induction of the Wnt transcriptional program during human stem cell differentiation. We show that long intermolecular 3'UTR-3'UTR interactions between Wnt transcription factor mRNAs and CTNNB1 enable co-translational protein complex assembly of these transcription factors with {beta}-catenin. As antisense oligonucleotide-mediated blocking of 3'UTR interactions impairs Wnt program induction, our findings indicate that transcriptional regulators can form functional units during protein biogenesis to be fully active.

cell biology↗

bioRxiv2024

Receptor tyrosine kinase inhibition leads to regression of acral melanoma by targeting the tumor microenvironment

Acral melanoma (AM) is an aggressive melanoma variant that arises from palmar, plantar, and nail unit melanocytes. Compared to non-acral cutaneous melanoma (CM), AM is biologically distinct, has an equal incidence across genetic ancestries, typically presents in advanced stage disease, is less responsive to therapy, and has an overall worse prognosis. Independent analysis of published genomic and transcriptomic sequencing identified that receptor tyrosine kinase (RTK) ligands and adapter proteins are frequently amplified, translocated, and/or overexpressed in AM. To target these unique genetic changes, a zebrafish acral melanoma model was exposed to a panel of narrow and broad spectrum multi-RTK inhibitors, revealing that dual FGFR/VEGFR inhibitors decrease acral-analogous melanocyte proliferation and migration. The potent pan-FGFR/VEGFR inhibitor, Lenvatinib, uniformly induces tumor regression in AM patient-derived xenograft (PDX) tumors but only slows tumor growth in CM models. Unlike other multi-RTK inhibitors, Lenvatinib is not directly cytotoxic to dissociated AM PDX tumor cells and instead disrupts tumor architecture and vascular networks. Considering the great difficulty in establishing AM cell culture lines, these findings suggest that AM may be more sensitive to microenvironment perturbations than CM. In conclusion, dual FGFR/VEGFR inhibition may be a viable therapeutic strategy that targets the unique biology of AM.

cancer biology↗

bioRxiv2021

Targeting an anchored phosphatase-deacetylase unit restores renal ciliary homeostasis.

Pathophysiological defects in water homeostasis can lead to renal failure. Autosomal dominant polycystic kidney disease (ADPKD) is a common genetic disorder associated with abnormal cytoskeletal dynamics in the kidney collecting ducts and perturbed calcium and cAMP signaling in the ciliary compartment. We show that collecting ducts in mice lacking the A-Kinase anchoring protein AKAP220 exhibit enhanced development of primary cilia. Mechanistic studies reveal that AKAP220-associated protein phosphatase 1 (PP1) mediates this phenotype by promoting changes in the stability of histone deacetylase 6 (HDAC6) with concomitant defects in actin dynamics. This proceeds through a previously unrecognized adaptor function for PP1 as all ciliogenesis and cytoskeletal phenotypes are recapitulated in mIMCD3 knock-in cells expressing a phosphatase-targeting defective AKAP220-{Delta}PP1 mutant. Pharmacological blocking of local HDAC6 activity alters cilia development and reduces cystogenesis in kidney-on-chip and organoid models of ADPKD. These findings identify the AKAP220-PPI-HDAC6 pathway as a key effector in primary cilia development.

cell biology↗