關于正常二倍體細胞的復制性衰老期間對P16和P53腫瘤抑制基因的選擇性剪接報道有所增加,，但是多數(shù)轉錄物的生物學功能仍然是未知的。研究發(fā)現(xiàn)ING1后生調節(jié)器的一個剪接產(chǎn)物，ING1a,，它在衰老過程中也增加,，而且,，在其他生長感受態(tài)細胞中ING1被迫表達的這種水平能夠引起衰老,。

這項研究中確定了一個主要機制，ING1a引起的衰老是通過抑制細胞吞噬作用;隨后激活視網(wǎng)膜母細胞瘤（RB）腫瘤抑制基因途徑,，通過增加視網(wǎng)膜母細胞瘤（RB）和預防它失活的復合機制,。此研究還建立了細胞內(nèi)吞作用和氧化應激之間的，而且提出復合機制,，誘導細胞衰老也可以通過抑制正常的內(nèi)吞作用,，從而影響正常信號傳遞途徑，包括細胞生長中那些必須的促有絲分裂途徑,。

原文摘要：

The ING1a Tumor Suppressor Regulates Endocytosis to Induce Cellular Senescence Via the Rb-E2F Pathway

Uma Karthika Rajarajacholan, Subhash Thalappilly, Karl Riabowol

The INhibitor of Growth （ING） proteins act as type II tumor suppressors and epigenetic regulators, being stoichiometric members of histone acetyltransferase and histone deacetylase complexes. Expression of the alternatively spliced ING1a tumor suppressor increases >10-fold during replicative senescence. ING1a overexpression inhibits growth; induces a large flattened cell morphology and the expression of senescence-associated β-galactosidase; increases Rb, p16, and cyclin D1 levels; and results in the accumulation of senescence-associated heterochromatic foci. Here we identify ING1a-regulated genes and find that ING1a induces the expression of a disproportionate number of genes whose products encode proteins involved in endocytosis. Intersectin 2 （ITSN2） is most affected by ING1a, being rapidly induced >25-fold. Overexpression of ITSN2 independently induces expression of the p16 and p57KIP2 cyclin-dependent kinase inhibitors, which act to block Rb inactivation, acting as downstream effectors of ING1a. ITSN2 is also induced in normally senescing cells, consistent with elevated levels of ING1a inducing ITSN2 as part of a normal senescence program. Inhibition of endocytosis or altering the stoichiometry of endosome components such as Rab family members similarly induces senescence. Knockdown of ITSN2 also blocks the ability of ING1a to induce a senescent phenotype, confirming that ITSN2 is a major transducer of ING1a-induced senescence signaling. These data identify a pathway by which ING1a induces senescence and indicate that altered endocytosis activates the Rb pathway, subsequently effecting a senescent phenotype.