p53 mitigates the effects of oncogenic HRAS in urothelial cells via the repression of MCOLN1

Jung, Jewon; Han, Liang; Coker, Shannon A.; Luan, Hong; Hancock, John F.; Denicourt, Catherine; Venkatachalam, Kartik

doi:10.1016/j.isci.2021.102701

Cited by 8 publications

(15 citation statements)

References 80 publications

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“…Mcoln1, inhibiting cancer cell proliferation and invasion. 54 Mutation or inactivation of p53, as observed in CLL, 55 augments Mcoln1 abundance, which fuels cancer progression. 54 Never in Mitosis gene A (NIMA)related kinase 6 (Nek6) was initially discovered as a regulator of mitotic cell division and inhibition of Nek6 results in apoptosis.…”

Section: Discussionmentioning

confidence: 99%

BAFF, but not APRIL, initiates Chronic Lymphocytic Leukemia by inducing tumor-promoting genes rather than cell survival.

Ullah

Garcillán

Whitlock

et al. 2023

Preprint

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Chronic Lymphocytic Leukemia (CLL) is the most common leukemia in adults, characterized by the expansion of CD19+ CD5+ B cells. The origin of CLL remains debated, with one model suggesting that CLL cells carrying mutations in the variable regions of immunoglobulin are derived from post-germinal center B cells, whereas unmutated CLL cells originate from CD5+ mature B cell precursors. The cytokines BAFF and APRIL each play a significant role in CLL cell survival and accumulation, but their involvement in disease initiation is unclear. Using the TCL1-transgenic (Tg) model, we have demonstrated that BAFF, but not, APRIL is needed for the initiation and dissemination of CLL. In the absence of BAFF or its receptor BAFF-R, expression of the TCL1 transgene increases CLL cell numbers in the peritoneal cavity but does not allow dissemination into the periphery. BAFF binding to BAFF-R is not required for the survival of peritoneal CLL cells but for the expression of tumor-promoting genes, likely allowing peritoneal CLL cells to disseminate to other sites to drive CLL. Our findings unveil BAFF as an unrecognized tumor-promoting cytokine in CLL. Combining current CLL therapies with BAFF inhibition may offer dual benefits: reducing peripheral tumor burden and suppressing transformed CLL cell output.

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Section: Discussionmentioning

confidence: 99%

BAFF, but not APRIL, initiates Chronic Lymphocytic Leukemia by inducing tumor-promoting genes rather than cell survival.

Ullah

Garcillán

Whitlock

et al. 2023

Preprint

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“…Many genes that encode endolysosomal ion channels, including TRPML1 and TPC2, are under the control of TFEB [ 211 , 212 , 226 , 227 ] ( Figure 6 ). In turn, nuclear translocation of TFEB, which is dependent on the phosphorylation status of the protein, is regulated by TRPML1 and TPC2 ( Figure 6 ).…”

Section: Regulation Of Lifespan By Ion Channels Involved In Autophagy...mentioning

confidence: 99%

“…While TFEB-driven autophagy and endolysosomal biogenesis delays aging via the clearance of toxic macromolecules, unremitting activation of TFEB can paradoxically shorten lifespan [ 141 ]. Either the overexpression and/or constitutive nuclear localization of TFEB and TFE3 promote the growth of various types of cancer [ 226 , 227 , 229 , 230 , 231 , 232 , 233 , 234 , 235 , 236 , 237 , 238 , 239 , 240 ]. Additionally, amplification of the MITF locus and functional upregulation of MITF are potent drivers of melanoma [ 213 , 241 , 242 , 243 , 244 , 245 , 246 ].…”

Section: Regulation Of Lifespan By Ion Channels Involved In Autophagy...mentioning

confidence: 99%

“…These findings point to the importance of maintaining autophagy and endolysosomal function at an optimal level because deviation from this optimum in either direction has deleterious consequences to healthy lifespan. In cancers driven by TFEB/TFE3/MITF, expression of genes encoding endolysosomal cation channels, TRPML1, TRPML2 and TPC2, is elevated, and either the knockdown or pharmacological inhibition of these channels attenuates the growth and invasiveness of the tumors [ 160 , 226 , 227 , 247 , 248 , 249 , 250 , 251 , 252 ]. Taken together, these studies point to the highly context-dependent relationship between endolysosomal ion channels and healthspan.…”

Section: Regulation Of Lifespan By Ion Channels Involved In Autophagy...mentioning

confidence: 99%

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Regulation of Aging and Longevity by Ion Channels and Transporters

Venkatachalam

2022

Cells

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Despite significant advances in our understanding of the mechanisms that underlie age-related physiological decline, our ability to translate these insights into actionable strategies to extend human healthspan has been limited. One of the major reasons for the existence of this barrier is that with a few important exceptions, many of the proteins that mediate aging have proven to be undruggable. The argument put forth here is that the amenability of ion channels and transporters to pharmacological manipulation could be leveraged to develop novel therapeutic strategies to combat aging. This review delves into the established roles for ion channels and transporters in the regulation of aging and longevity via their influence on membrane excitability, Ca2+ homeostasis, mitochondrial and endolysosomal function, and the transduction of sensory stimuli. The goal is to provide the reader with an understanding of emergent themes, and prompt further investigation into how the activities of ion channels and transporters sculpt the trajectories of cellular and organismal aging.

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“…Thus, TRPML1 overexpression has been found in cancer-bearing, oncogenic HRAS mutations [ 10 ], triple-negative breast cancer (TNBC) cell lines [ 11 ], melanomas [ 12 ], non-small-cell lung carcinomas (NSCLCs) [ 13 ], pancreatic adenocarcinomas (PDACs) [ 14 ] and p53-deficient bladder cancer [ 15 ]. Increased TRPML2 expression in HN31 oral cancer cells [ 10 ] and downregulation of the MCOLN2 gene, due to DNA methylation, in pediatric acute lymphoblastic leukemia [ 16 ], lung adenocarcinoma and squamous cell carcinoma [ 17 ] were reported.…”

Section: Introductionmentioning

confidence: 99%

Coexpression of TRPML1 and TRPML2 Mucolipin Channels Affects the Survival of Glioblastoma Patients

Santoni

Maggi

Amantini

et al. 2022

IJMS

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Among brain cancers, glioblastoma (GBM) is the most malignant glioma with an extremely poor prognosis. It is characterized by high cell heterogeneity, which can be linked to its high malignancy. We have previously demonstrated that TRPML1 channels affect the OS of GBM patients. Herein, by RT-PCR, FACS and Western blot, we demonstrated that TRPML1 and TRPML2 channels are differently expressed in GBM patients and cell lines. Moreover, these channels partially colocalized in ER and lysosomal compartments in GBM cell lines, as evaluated by confocal analysis. Interestingly, the silencing of TRPML1 or TRPML2 by RNA interference results in the decrease in the other receptor at protein level. Moreover, the double knockdown of TRPML1 and TRPML2 leads to increased GBM cell survival with respect to single-channel-silenced cells, and improves migration and invasion ability of U251 cells. Finally, the Kaplan–Meier survival analysis demonstrated that patients with high TRPML2 expression in absence of TRPML1 expression strongly correlates with short OS, whereas high TRPML1 associated with low TRPML2 mRNA expression correlates with longer OS in GBM patients. The worst OS in GBM patients is associated with the loss of both TRPML1 and TRPML2 channels.

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p53 mitigates the effects of oncogenic HRAS in urothelial cells via the repression of MCOLN1

Abstract: MCOLN1 expression is elevated in BLCA tumors lacking p53 p53 represses MCOLN1 in both normal and transformed urothelium MCOLN1 induction upon p53 loss augmented effects of mutant HRAS Loss of p53 and HRAS mutations predict addiction to TRPML1 in bladder cancer

Cited by 8 publications

References 80 publications

BAFF, but not APRIL, initiates Chronic Lymphocytic Leukemia by inducing tumor-promoting genes rather than cell survival.

BAFF, but not APRIL, initiates Chronic Lymphocytic Leukemia by inducing tumor-promoting genes rather than cell survival.

Regulation of Aging and Longevity by Ion Channels and Transporters

Coexpression of TRPML1 and TRPML2 Mucolipin Channels Affects the Survival of Glioblastoma Patients

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