The Role of p16INK4a Pathway in Human Epidermal Stem Cell Self-Renewal, Aging and Cancer

Abstract

The epidermis is a self-renewing tissue. The balance between proliferation and differentiation processes is tightly regulated to ensure the maintenance of the stem cell (SC) population in the epidermis during life. Aging and cancer may be considered related endpoints of accumulating damages within epidermal self-renewing compartment. p16INK4a is a potent inhibitor of the G1/S-phase transition of the cell cycle. p16INK4a governs the processes of SC self-renewal in several tissues and its deregulation may result in aging or tumor development. Keratinocytes are equipped with several epigenetic enzymes and transcription factors that shape the gene expression signatures of different epidermal layers and allow dynamic and coordinated expression changes to finely balance keratinocyte self-renewal and differentiation. These factors converge their activity in the basal layer to repress p16INK4a expression, protecting cells from senescence, and preserving epidermal homeostasis and regeneration. Several stress stimuli may activate p16INK4a expression that orchestrates cell cycle exit and senescence response. In the present review, we discuss the role of p16INK4a regulators in human epidermal SC self-renewal, aging and cancer.

Functional anatomy of the hair follicle: The Secondary Hair Germ

“…The same study has identified p16 (Ink4a), an alternatively spliced variant of the Cdkn2a gene product, as a protein highly expressed in the telogen SHG and not present in the bulge. P16 orchestrates the cell cycle exit by blocking the G1 to S phase transition . Its activity restrains the proliferation of islet cells and of basal epidermal keratinocytes .…”

“…P16 orchestrates the cell cycle exit by blocking the G1 to S phase transition . Its activity restrains the proliferation of islet cells and of basal epidermal keratinocytes . These features make p16 an attractive candidate for restraining cell proliferation in the SHG, especially at the terminal (or “competent”) phase of telogen, when SHG cells show obvious signs of activation ( see also Supplementary text ).…”

Compromising the constitutive p16INK4a expression sensitizes human neuroblastoma cells to Hsp90 inhibition and promotes premature senescence

“…For this reason, we went ahead examining the downstream regulators such as CDK4 and CDK6. The kinase CDK6 is not only implicated in cancer for its oncogenic role, but for regulating the stem cell pool dynamics that facilitates recurrence . Altered stem cell marker expressions in response to KD and Hsp90 inhibition in matrix based manner (2D vs 3D) suggests their independent influence on regulating the stem cell pool dynamics.…”

“…The kinase CDK6 is not only implicated in cancer for its oncogenic role, but for regulating the stem cell pool dynamics that facilitates recurrence. 31,33,34 Altered stem cell marker expressions in response to KD and Hsp90 inhibition in matrix based manner (2D vs 3D) suggests their independent influence on regulating the stem cell pool dynamics. However, in KD combination with 17AAG, this regulation is found to be lost.…”

Mapping of human papilloma virus, p16, and epstein‐barr virus in non‐malignant tonsillar disease

“…The HPV oncoprotein E7 binds to and inhibits the retinoblastoma protein pRb which leads to release of transcription factor E2F which in return leads to progression to S phase in the cell cycle. As cells divide, levels of p16 rise in an attempt to control cell division in HPV infected cells which cannot succeed as its mechanism of action is being surpassed …”