β-Arrestin-1 links mitogenic sonic hedgehog signaling to the cell cycle exit machinery in neural precursors

Abstract

Development of the cerebellum, a brain region regulating posture and coordination, occurs post-natally and is marked by rapid proliferation of granule neuron precursors (CGNPs), stimulated by mitogenic Sonic hedgehog (Shh) signaling. β-Arrestin (βArr) proteins play important roles downstream of Smoothened, the Shh signal transducer. However, whether Shh regulates βArrs and what role they play in Shh-driven CGNP proliferation remains to be determined. Here, we report that Shh induces βArr1 accumulation and localization to the nucleus, where it participates in enhancing expression of the cyclin dependent kinase (cdk) inhibitor p27, whose accumulation eventually drives CGNP cell cycle exit. βArr1 knockdown enhances CGNP proliferation and reduces p27 expression. Thus, Shh-mediated βArr1 induction represents a novel negative feedback loop within the Shh mitogenic pathway, such that ongoing Shh signaling, while required for CGNPs to proliferate, also sets up a cell-intrinsic clock programming their ultimate exit from the cell cycle.

An essential role for p38 MAPK in cerebellar granule neuron precursor proliferation

“…ESM 1b). Transcripts, such as Gli1 , that are direct targets of Gli2/3 downstream of Shh have been shown to increase rapidly at these early time points and remain elevated throughout the 48 hours of culture [46]. In contrast, we did not observe any significant changes in p38 mRNA levels with or without Shh.…”

“…This will also be critical for developing new targeted therapies to treat medulloblastoma patients that will both increase their survival rate and ameliorate the life-long, debilitating side effects that occur as a result of the current standard of care (surgical resection, craniospinal radiation, chemotherapy). Mitogen-Activated Protein Kinases (MAPKs) play a prominent role in regulating proliferation in all mammalian cells and Shh has been noted to act very much like a classic mitogen [27,46,59]. Moreover, classic MAP/Erk kinase pathway activity is known to be required for long-term CGNP survival, albeit dispensable for short-term CGNP proliferation [6,27].…”

β-arrestin-1 is a nuclear transcriptional regulator of endothelin-1-induced β-catenin signaling

“…[3][4][5][6][7][8][9][10][11][12] A global proteomics analysis of b-arr1-interacting proteins demonstrated that b-arr1 interactions take place not only in the cytoplasm, but also in the nucleus, 13 suggesting that b-arr1 has a role in transcriptional regulation in different human cells. [14][15][16] Previous studies indicate that under d-or k-opioid receptor stimulations, nuclear b-arr1 specifically accumulates at p27 and c-fos promoters through scaffolding cyclic adenosine monophosphate responseelement (CRE) binding protein and histone acetyltransferase p300, thus enhancing local histone acetylation and gene transcription. 17 A similar mechanism was also observed during T-cell activation, in which nuclear b-arr1 increases Bcl-2 expression and contributes to CD4 þ T-cell survival.…”

Co-expression of β-arrestin1 and NF-кB is associated with cancer progression and poor prognosis in lung adenocarcinoma

“…A global proteomic analysis also demonstrated that β-arrestin1 is distributed in the cytoplasm as well as in the nucleus [6]. These give investigators a new inspiration that β-arrestin1 plays a vital role in transcriptional regulation in cell growth, apoptosis, and modulation of immune functions [7][8][9]. Meanwhile, there are increasing evidences that nuclear β-arrestin1 contributes to tumor growth, invasion, and metastasis in multiple malignancies such as breast cancer, colorectal cancer, lung cancer, and prostate cancer [10][11][12][13].…”