Defining master transcription factors governing somatic and cancer stem cell identity is an important goal. Here we show that the Oct4 paralog Oct1, a transcription factor implicated in stress responses, metabolic control, and poised transcription states, regulates normal and pathologic stem cell function. Oct1HI cells in the colon and small intestine co-express known stem cell markers. In primary malignant tissue, high Oct1 protein but not mRNA levels strongly correlate with the frequency of CD24LOCD44HI cancer-initiating cells. Reducing Oct1 expression via RNAi reduces the proportion of ALDHHI and dye effluxHI cells, and increasing Oct1 increases the proportion of ALDHHI cells. Normal ALDHHI cells harbor elevated Oct1 protein but not mRNA levels. Functionally, we show that Oct1 promotes tumor engraftment frequency and promotes hematopoietic stem cell engraftment potential in competitive and serial transplants. In addition to previously described Oct1 transcriptional targets, we identify four Oct1 targets associated with the stem cell phenotype. Cumulatively, the data indicate that Oct1 regulates normal and cancer stem cell function.

Inactivation of maturation-promoting factor [(MPF) Cdk1/Cyclin B]is a key event in the exit from mitosis. Although degradation of Cyclin B is important for MPF inactivation, recent studies indicate that Cdk1 phosphorylation and inactivation occur before Cyclin B degradation and, therefore, also may be important steps in the exit from mitosis. Cdk1 activity is controlled by the Cdc25C phosphatase, which is turned on at the G 2/M transition to catalyze Cdk1 activation. PP2A:B56␦ is a negative regulator of Cdc25C during interphase. We show here that PP2A:B56␦ also regulates Cdc25C at mitosis. Failure of PP2A:B56␦ to dephosphorylate Cdc25C at mitosis results in prolonged hyperphosphorylation and activation of Cdc25C, causing persistent dephosphorylation and, hence, activation of Cdk1. This constitutive activation of Cdc25C and Cdk1 leads to a delayed exit from mitosis. Consistent with Cdk1 as a major biological target of B56␦, stable knockdown and germ-line mouse KO of B56␦ leads to compensatory transcriptional up-regulation of Wee1 kinase to oppose the Cdc25C activity and permit cell survival. These observations place PP2A:B56␦ as a key upstream regulator of Cdk1 activity upon exit from mitosis.cell cycle ͉ cyclins ͉ protein phosphatase ͉ knockout ͉ Wee1

The tumor suppressor BRCA1 regulates the DNA damage response (DDR) and other processes that remain incompletely defined. Among these, BRCA1 heterodimerizes with BARD1 to ubiquitylate targets via its N-terminal E3 ligase activity. Here, it is demonstrated that BRCA1 promotes oxidative metabolism by degrading Oct1 (POU2F1), a transcription factor with proglycolytic and tumorigenic effects. BRCA1 E3 ubiquitin ligase mutation skews cells toward a glycolytic metabolic profile while elevating Oct1 protein. CRISPR-mediated Oct1 deletion reverts the glycolytic phenotype. RNA sequencing (RNAseq) confirms deregulation of metabolic genes downstream of Oct1. BRCA1 mediates Oct1 ubiquitylation and degradation, and mutation of two ubiquitylated Oct1 lysines insulates the protein against BRCA1-mediated destabilization. Oct1 deletion in MCF-7 breast cancer cells does not perturb growth in standard culture, but inhibits growth in soft agar and xenograft assays. In primary breast cancer clinical specimens, Oct1 protein levels correlate positively with tumor aggressiveness and inversely with BRCA1. These results identify BRCA1 as an Oct1 ubiquitin ligase that catalyzes Oct1 degradation to promote oxidative metabolism and restrict tumorigenicity. .

When faced with conflicts, social media platforms harken back to their front-facing, user-friendly documents. These documents, often called community standards, or something similar, lay out the practices allowed on their sites. It is well documented in legal scholarship how technology companies incorporate particular First Amendment jurisprudence into these community standards documents, and this work aims to empirically examine this claim. Specifically, we were interested in how the backbone of American free expression—the marketplace of ideas metaphor—was incorporated into these governing documents. We conducted a textual analysis of five US-based social media platforms (Facebook, Twitter, YouTube, Instagram, and Tumblr) to analyze how the marketplace of ideas metaphor may be invoked. We found these documents do rely heavily on the metaphor for presenting governing strategies. They also rely heavily on an oft-referenced ambiguous moderation line and the idea of a singular, global, borderless community, both of which bolster the marketplace metaphor. Given this, US-based social media platforms are holding the rest of the world to US-based ideas of free expression, thus engaging in digital manifest destiny.